New compounds

ABSTRACT

The present invention relates to compounds of the general formula (I),  
                 
 
     wherein P is sulfone or sulfonamide; and  
     A, B, W, X, Y and R 3  are as defined in the description; to pharmaceutical compositions comprising these compounds, and to the use of the compounds for the prophylaxis and treatment of medical conditions relating to obesity, type II diabetes, and/or CNS disorders, to achieve reduction of body weight and of body weight gain.

RELATED APPLICATIONS

[0001] This application claims priority to Swedish application number0201925-5, filed on Jun. 20, 2002, Swedish application number 0202908-0,filed on Oct. 1, 2002, Swedish application number 0202181-4, filed onJul. 11, 2002, Swedish application number 0300357-1, filed on Feb. 10,2003, U.S. provisional application No. 60/406,120, filed on Aug. 26,2002, U.S. provisional application No. 60/434,010, filed on Dec. 17,2002, and U.S. provisional application No. 60/464,701, filed on Apr. 23,2003, the contents of which are incorporated herein by reference.

TECHNICAL FIELD

[0002] The present invention relates to substituted sulphone andsulphonamide compounds, to pharmaceutical compositions comprising thesecompounds, and to the use of the compounds for the prophylaxis andtreatment of medical conditions relating to obesity, type 2 diabetes,and/or disorders of the central nervous system (CNS), to achievereduction of body weight and of body weight gain, as well as forcosmetic use.

BACKGROUND ART

[0003] Obesity is a condition characterized by an increase in body fatcontent resulting in excess body weight above accepted norms. Obesity isthe most important nutritional disorder in the western world andrepresents a major health problem in all industrialized countries. Thisdisorder leads to increased mortality due to increased incidences ofdiseases such as cardiovascular disease, digestive disease, respiratorydisease, cancer and type 2 diabetes. Searching for compounds, whichreduce body weight has been going on for many decades. One line ofresearch has been activation of serotoninergic systems, either by directactivation of serotonin receptor subtypes or by inhibiting serotoninreuptake. The exact receptor subtype profile required is however notknown.

[0004] Serotonin (5-hydroxytryptamine or 5-HT), a key transmitter of theperipheral and central nervous system, modulates a wide range ofphysiological and pathological functions, including anxiety, sleepregulation, aggression, feeding and depression. Multiple serotoninreceptor subtypes have been identified and cloned. One of these, the5-HT₆ receptor, was cloned by several groups in 1993 (Ruat, M. et al.(1993) Biochem. Biophys. Res. Commun.193: 268-276; Sebben, M. et al.(1994) NeuroReport 5: 2553-2557). This receptor is positively coupled toadenylyl cyclase and displays affinity for antidepressants such asclozapine. Recently, the effect of 5-HT₆ antagonist and 5-HT₆ antisenseoligonucleotides to reduce food intake in rats has been reported(Bentley, J. C. et al. (1999) Br J Pharmac. Suppl. 126, P66; Bentley, J.C. et al. (1997) J. Psychopharmacol. Suppl. A64, 255; Woolley M. L. etal. (2001) Neuropharmacology).

[0005] Compounds with enhanced affinity and selectivity for the 5-HT₆receptor have been identified, e.g. in WO 00/34242 and by Isaac, M. etal. (2000) 6-Bicyclopiperazinyl-1-arylsulfonylindoles and6-Bicyclopiperidinyl-1-arylsulfonylindoles derivatives as novel, potentand selective 5-HT₆ receptor antagonists. Bioorganic & MedicinalChemistry Letters 10: 1719-1721 (2000).

Information Disclosure

[0006] J. Med. Chem. 1970, 13(4), 592-598 describesN-(4-{[2-(diethylamino)ethyl]amino}-1-naphthyl)amides;N-{5,6,7,8-Tetrahydro-4-[(3-piperidinopropyl)amino]-1-naphthyl}amidesand related amides and urea derivatives as schistosomicides.

[0007] WO 99/42465 discloses sulphonamides derivatives that bind to the5-HT₆ receptor and that can be used for the treatment of CNS disorderssuch as anxiety, depression, epilepsy, obsessive compulsive disorders,cognitive disorders, ADHD, anorexia and bulimia schizophrenia, drugabuse.

[0008] WO 01/32646 A1 discloses compounds that bind to the 5-HT₆receptor and that are used for the treatment of CNS disorders and whichinter alia may be used for the treatment of eating disorders.

[0009] WO 99/37623 A2 discloses compounds that bind to the 5-HT₆receptor and that are used for the treatment of CNS disorders and whichinter alia may be used for the treatment of eating disorders.

[0010] WO 99/42465 A3 discloses compounds that bind to the 5-HT₆receptor and that are used for the treatment of CNS disorders and whichinter alia may be used for the treatment of eating disorders.

[0011] EP 0 815 861 A1 discloses compounds that bind to the 5-HT₆receptor and that are used for the treatment of CNS disorders.

[0012] WO 99/02502 A2 discloses compounds that bind to the 5-HT₆receptor and that are used for the treatment of CNS disorders and whichinter alia may be used for the treatment of eating disorders.

[0013] WO 98/27081 A1 discloses compounds that bind to the 5-HT₆receptor and that are used for the treatment of CNS disorders and whichinter alia may be used for the treatment of eating disorders.

[0014] EP 0701819 discloses compounds that bind to the 5-HT_(1D)receptor and that are used for the treatment of CNS disorders andobesity.

[0015] U.S. Pat. No. 6,191,141 and WO 01/12629 disclose compounds thatbind to the 5-HT₆ receptor and that are used for the treatment of CNSdisorders.

DISCLOSURE OF THE INVENTION

[0016] It has surprisingly been found that the compounds of formula (I)show affinity for the 5-HT₆ receptor as antagonists at low nanomolarrange. Compounds according to the invention and their pharmaceuticallyacceptable salts have 5-HT₆ receptor antagonist, agonist and partialagonist activity and are believed to be of potential use in thetreatment or prophylaxis of obesity and type 2 diabetes, to achievereduction of body weight and of body weight gain, as well as in thetreatment or prophylaxis of disorders of the central nervous system suchas anxiety, depression, panic attacks, memory disorders, cognitivedisorders, sleep disorders, migraine, anorexia, bulimia, bingedisorders, obsessive compulsive disorders, psychoses, Alzheimer'sdisease, Parkinson's disease, Huntington's chorea and/or schizophrenia,Attention Deficit Hyperactive Disorders (ADHD), drug abuse. Thereduction of body weight and of body weight gain (e.g. treatingbody-weight disorders) is achieved inter alia by reduction of foodintake. As used herein, the term “body weight disorders” refers to thedisorders caused by an imbalance between energy intake and energyexpenditure, resulting in abnormal body (e.g., excessive) weight. Suchbody weight disorders include obesity.

Definitions

[0017] Unless otherwise stated or indicated, the term “C₁₋₆ alkyl” (or“C₂₋₆ alkenyl”) denotes a straight or branched hydrocarbon chain grouphaving from 1 to 6 carbon atoms (or 2 to 6 carbon atoms). Examples ofsaid lower alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl,iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyland hexyl. Alkenyl groups have one or more double carbon-carbon bonds inthe chain.

[0018] Unless otherwise stated or indicated, the term “C₁₋₆ alkoxy”denotes a straight or branched alkoxy group having from 1 to 6 carbonatoms. Examples of said lower alkoxy include methoxy, ethoxy, n-propoxy,iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight-and branched-chain pentoxy and hexoxy.

[0019] Unless otherwise stated or indicated, the term “C₁₋₆ alkoxyalkyl”denotes a straight or branched alkoxyalkyl group having from 1 to 6carbon atoms. Examples of said lower alkoxyalkyl include methoxymethyl,ethoxymethyl, iso-propoxymethyl, n-butoxymethyl, t-butoxyethyl andstraight- and branched-chain pentoxymethyl.

[0020] The expression “C₂₋₆ alkenyl” as used herein refers tostraight-chained and branched alkenyl groups containing from 2 to 6carbon atoms. Typical examples include vinyl, allyl, 2,3-dimethylallyl,1-butenyl groups, 1-pentenyl, and 1-hexenyl groups.

[0021] The expression “C₂₋₆ alkynyl” as used herein refers tostraight-chained and branched alkynyl groups containing from 2 to 6carbon atoms. Typical examples include ethynyl, 1-propynyl, 1-butynyl,1-pentynyl, and 1-hexynyl groups.

[0022] Unless otherwise stated or indicated, the term “halogen” shallmean fluorine, chlorine, bromine or iodine.

[0023] The term “alkylhalide” refers to an alkyl group substituted withone or more halogen groups (e.g., F, Cl, Br, I).

[0024] The term “C₃₋₇ cycloalkyl” denotes a cyclic alkyl group having aring size from C₃ to C₇, which can be saturated or partiallyunsaturated. Examples of said cycloalkyl include cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl,methylcyclohexyl, cyclohexenyl, cyclohexadienyl, and cycloheptyl.

[0025] The term “C₅₋₁₀ cycloalkenyl” denotes a cyclic alkenyl grouphaving a ring size from C₅ to C₁₀. Examples of said cycloalkenyl include1-cyclopentyl, 2-cyclopentenyl, 1-cyclohexenyl, 1-cyclohepentyl,1-cyclooctenyl, 1-cyclononenyl, and 1-cyclodecenyl groups.

[0026] The term “heterocyclic” refers to a hydrocarbon ring systemcontaining 4 to 8 ring members that have at least one heteroatom (e.g.,S, N, or O) as part of the ring. It includes saturated, unsaturated,aromatic, and nonaromatic heterocycles. Suitable heterocyclic groupsinclude thienyl, furyl, pyridyl, pyrrolidinyl, imidazolyl, pyrazolyl,piperidyl, azepinyl, morpholinyl, pyranyl, dioxanyl, pyridazinyl,pyrimidinyl, and piperazinyl groups

[0027] Unless otherwise stated or indicated, the term “aryl” refers to ahydrocarbon ring system having at least one aromatic ring. Examples ofaryl groups include phenyl, cinnamyl, pentalenyl, indenyl, 1-naphthyl,2-naphthyl, anthryl and phenanthryl.

[0028] The term “heteroaryl” refers to a hydrocarbon ring system havingat least one aromatic ring which contains at least one heteroatom suchas O, N, or S. Examples of heteroaryl groups include furyl, pyrrolyl,thienyl, oxazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl,quinazolinyl, and indolyl groups.

Compounds of Formula (I)

[0029] One object of the present invention is a compound having thegeneral formula (I):

[0030] or a pharmaceutically acceptable salt thereof, wherein:

[0031] ring B is

[0032]  in which D is a five-membered heterocyclic or heteroaryl ring,said heteroaryl ring comprising one or two atoms selected from the groupconsisting of nitrogen, sulfur and oxygen, with the proviso that when Dcontains an oxygen atom, D is heteroaryl;

[0033] each W is independently —N—, —(CH)—, or —C— provided that notmore than three groups W are —N— in both rings A and B together;

[0034] P is any one of formula (a), (b) or (c)

[0035] wherein x=0, 1, or 2 and y=0, 1, or 2;

[0036] and P and R³ can be attached to any carbon atom that allows thesubstitution in one of either the A- or B-ring, or when ring A containsat least one nitrogen atom and P is (c), then P can also be attached toany nitrogen in ring B that allows the substitution;

[0037] the dashed bonds denote that P and R³, respectively, may beattached to either the A or B ring; but each P or R³ may not besimultaneously bound to both rings A and B;

[0038] R¹ is

[0039] (a) C₁₋₆ alkyl,

[0040] (b) C₁₋₆ alkoxyalkyl,

[0041] (c) straight-chained or branched C₁₋₆ hydroxyalkyl,

[0042] (d) straight-chained or branched C₁₋₆ alkylhalides,

[0043] (e) aryl carbonylmethyl,

[0044] (f) C₃₋₇ cycloalkyl, which is optionally partially unsaturated,

[0045] (g) C₃₋₇ cycloalkyl-C₁₋₆ alkyl, wherein the cyclic ring isoptionally partially unsaturated, or

[0046] (h) a group Ar;

[0047] wherein Ar is

[0048] (a) phenyl,

[0049] (b) 1-naphthyl,

[0050] (c) 2-naphthyl,

[0051] (d) aryl-C₁₋₆ alkyl,

[0052] (e) cinnamyl,

[0053] (f) a 5 to 7-membered, optionally aromatic, partially saturatedor completely saturated, mono- or bi-cyclic heterocyclic ring, eachcontaining 1 to 4 heteroatoms, selected from oxygen, sulfur, andnitrogen,

[0054] (g) a bicyclic ring system comprising at least one heterocyclicring according to (f) and a group Ar,

[0055] wherein the group Ar is substituted in one or more positions with

[0056] (a) H, X or Y, or

[0057] (b) a 5 to 7-membered, optionally aromatic, partially saturatedor completely saturated, heterocyclic ring each containing 1 to 4heteroatoms selected from oxygen, nitrogen or sulfur;

[0058] R² is

[0059] (a) H,

[0060] (b) C₁₋₆ alkyl,

[0061] (c) C₂₋₆ alkoxyalkyl,

[0062] (d) straight or branched C₁₋₆ hydroxyalkyl, or

[0063] (e) straight or branched C₁₋₆ alkylhalides;

[0064] (f) a group Ar,

[0065] or R¹ and R² are linked to form a group —CH₂CH₂OCH₂CH₂— or

[0066] wherein v is 0-2,

[0067] X and Y are independently

[0068] (a) H,

[0069] (b) halogen,

[0070] (c) C₁₋₆ alkyl,

[0071] (d) CF₃,

[0072] (e) hydroxy,

[0073] (f) C₁₋₆ alkoxy,

[0074] (g) C₂₋₆ alkenyl,

[0075] (h) phenyl,

[0076] (i) phenoxy,

[0077] (j) benzyloxy,

[0078] (k) benzoyl,

[0079] (l) —OCF₃,

[0080] (m) —CN,

[0081] (n) straight or branched C₁₋₆ hydroxyalkyl,

[0082] (o) straight or branched C₁₋₆ alkylhalides,

[0083] (p) —NH₂,

[0084] (q) —NHR⁴,

[0085] (r) —NR⁴R,

[0086] (s) —NO₂,

[0087] (t) —CONR⁴R⁵,

[0088] (u) —NHSO₂R⁴,

[0089] (v) —NR⁴COR⁵,

[0090] (x) —SO₂NR⁴R⁵,

[0091] (z) —C(═O)R⁴,

[0092] (aa) —CO₂R⁴, or

[0093] (ab) —S(O)_(n)R⁴, wherein n is 0, 1, 2 or 3,

[0094] (ac) —S—(C₁₋₆) alkyl, or

[0095] (ad) —SCF₃; and

[0096] R⁴ and R⁵ are independently

[0097] (a) H,

[0098] (b) C₁₋₆ alkyl,

[0099] (c) C₃₋₇ cycloalkyl, or

[0100] (d) Ar, as defined above for R¹;

[0101] alternatively, R⁴ and R⁵ are linked to form a group —CH₂OCH₂—,—CH₂CH₂OCH₂CH₂— or (CH₂)₃₋₅;

[0102] R³ is a group selected from any one of

[0103] wherein R³ is optionally substituted on each carbon atom thatallows the substitution with Rq groups, wherein Rq is independently H,or (C₁₆) alkyl, and wherein two Rq groups can be present on the samecarbon atom simultaneously, wherein

[0104] q=1, 2, 3, 4, 5 or 6,

[0105] m=1 or 2, and

[0106] n=0, 1 or 2;

[0107] R is independently

[0108] (a) H,

[0109] (b) linear or branched C₁₋₆ alkyl,

[0110] (c) benzyl,

[0111] (d) —CH₂—CH₂—OH, or

[0112] (e) —CH₂—CH₂—O—C₁₋₆ alkyl;

[0113] P and R³ can be attached to the same ring or to different ringsof rings A and B;

[0114] provided that

[0115] when P is

[0116]  and P and R³ both are attached to ring A in the meta- orpara-position relative to one another then R³ is selected from any oneof

[0117] when ring B is

[0118]  and P is

[0119]  then P and R³ are simultaneously attached to the same ring A orB;

[0120] when ring B is

[0121]  and P is

[0122]  wherein y=0 then P and R³ are attached to the different rings ofrings A and B;

[0123] when the ring system A+B is benzofurane or benzothiophene, and Pis

[0124] and attached to position 3 in the A+B ring system, and R³ is agroup selected from any one of

[0125] and attached to position 7 in the A+B ring system, then y=1 or 2;

[0126] when the ring system A+B is indole, and P is

[0127] and P is attached to position 3 in the A+B ring system, and R³ isa group selected from any one of

[0128] and R³ is attached to any one of positions 5, 6 or 7 in the A+Bring system, then y=1 or 2; or

[0129] when ring B is

[0130]  and R¹=Ar is partially saturated bi-cyclic heterocyclic ringcontaining a N atom, the N atom in Ar cannot be attached to the S atomin P;

[0131] with the proviso that:

[0132] when rings A and B are both phenyl, P is any one of formula (a)or (c) substituted in position 7 on the naphthalene ring, then R³ is notsubstituted in position 1 on the naphthalene ring; and

[0133] with the proviso that:

[0134] when ring D is a pyrrole ring, P is of the formula (c), then R³is not of the formula

[0135] substituted in position 3 on the pyrrole ring.

[0136] A naphthalene ring has the following position numbers:

[0137] wherein P₁—P₈ denote the position on the naphthalene ring.

[0138] A pyrrole ring, as connected to an A ring, has the followingposition numbers:

[0139] wherein P₁—P₃ denote the position on the pyrrole ring.

[0140] It is preferred that:

[0141] R¹ is

[0142] (a) C₁₋₆ alkyl, or

[0143] (e) a group Ar;

[0144] Ar is

[0145] (a) phenyl,

[0146] (b) 1-naphthyl,

[0147] (c) 2-naphthyl, or

[0148] (f) a 5 to 7-membered, optionally aromatic, partially saturatedor completely saturated, heterocyclic ring containing 1 to 4heteroatoms, selected from oxygen, nitrogen and sulfur,

[0149] wherein the group Ar is substituted in one or more positions with

[0150] (a) H,

[0151] (b) halogen,

[0152] (c) C₁₋₆ alkyl,

[0153] (d) —CF₃,

[0154] (f) C₁₋₆ alkoxy,

[0155] (g) C₂₋₆ alkenyl (preferably C₂₋₄ alkenyl),

[0156] (l) —OCF₃,

[0157] (m) straight or branched C₁₋₆ hydroxyalkyl,

[0158] (n) phenyloxy,

[0159] (o) benzyloxy,

[0160] (v) —NR⁴COR⁵,

[0161] (x) —SO₂NR⁴R⁵,

[0162] (z) —C(═O)R⁴,

[0163] (ab) —S(O)_(n)R⁴, wherein n is 0, 1, 2 or 3;

[0164] (ac) —S—(C₁₋₆) alkyl, or

[0165] (ad) —SCF₃;

[0166] R² is

[0167] (a) H, or

[0168] (b) C₁₋₆ alkyl;

[0169] or R¹ and R² are linked to form a group —CH₂CH₂OCH₂CH₂—;

[0170] X and Y are H;

[0171] R⁴ and R⁵ are each independently H or C₁₋₃ alkyl; and

[0172] R³ is selected from any one of

[0173] wherein R³ can be substituted on each carbon atom that allows thesubstitution with Rq groups, wherein Rq is independently H, or C₁₋₆alkyl, and wherein two Rq groups can be present on the same carbon atomsimultaneously, wherein

[0174] q=1 or 2,

[0175] m=1 or 2,

[0176] n=0, and

[0177] R⁶ is independently

[0178] (a) H,

[0179] (b) C₁₋₆ alkyl (preferably C₁₋₃ alkyl), in particular methyl,

[0180] (d) —CH₂—CH₂—OH, or

[0181] (e) —CH₂—CH₂—OCH₃.

[0182] It is especially preferred that R³ is selected from any one of

[0183] wherein R³ can be substituted on each carbon atom that allows thesubstitution with Rq groups, wherein Rq is independently H, or C₁₋₂alkyl, and wherein two Rq groups can be present on the same carbon atomsimultaneously, wherein

[0184] q=1 or 2,

[0185] m=1 or 2; and

[0186] R⁶ is independently

[0187] (a) H,

[0188] (b) C₁₋₃ alkyl,

[0189] (d) —CH₂—CH₂—OH, or

[0190] (e) —CH₂—CH₂—OCH₃.

[0191] It is also preferred that R³ is selected from any one of

[0192] wherein R³ can be substituted on each carbon atom that allows thesubstitution with Rq groups, wherein Rq is independently H, or C₁₋₆alkyl, and wherein two Rq groups can be present on the same carbon atomsimultaneously, wherein

[0193] q=1 or 2,

[0194] m=1 or 2,

[0195] n=0, and

[0196] R⁶ is independently

[0197] (a) H,

[0198] (b) C₁₋₃ alkyl,

[0199] (d) —CH₂—CH₂—OH, or

[0200] (e) —CH₂—CH₂—OCH₃.

[0201] It is also preferred that R³ is selected from any one of

[0202] R⁶ is independently

[0203] (a) H,

[0204] (b) C₁₋₃ alkyl,

[0205] (d) —CH₂—CH₂—OH, or

[0206] (e) —CH₂—CH₂—OCH₃.

[0207] It is preferred that R⁶ is H or methyl.

[0208] It is also preferred that R³ is piperazine; homopiperazine;2,6-dimethylpiperazine; 3,5-dimethylpiperazine; 2,5-dimethylpiperazine;2-methylpiperazine; 3-methylpiperazine; 2,2-dimethylpiperazine;3,3-dimethylpiperazine; piperidine; 1,2,3,6-tetrahydro-pyrazine; or4-pyrrolidin-3-yloxy.

[0209] It is preferred that the groups Y and X are attached to anyunsubstituted carbon atom.

[0210] It is preferred that D is pyrrolyl, thienyl or furanyl.

[0211] It is preferred that P is

[0212] wherein R¹, x, and y are as defined in claim 1.

[0213] It is also preferred that P is

[0214] wherein R¹ and R² are as defined in claim 1.

[0215] It is preferred that R² is H.

[0216] Another object of the present invention is a compound of thegeneral formula (II)

[0217] wherein R¹, x, y, X, and Y are as defined in claim 1, and R³ isas defined in claim 2.

[0218] It is preferred that y=0 and x=2.

[0219] Another object of the present invention is a compound of thegeneral formula (III)

[0220] wherein R¹, x, y, X, and Y are as defined in claim 1, and R³ isas defined in claim 2.

[0221] It is preferred that y=0 and x=2

[0222] Another object of the present invention is a compound of thegeneral formula (IV)

[0223] wherein P is of the formula (c), R¹, x, y, X, and Y are asdefined in claim 1, and R³ is as defined in claim 2, and

[0224] wherein D is a five-membered heteroaryl ring, said ringcomprising one or two atoms selected from the group consisting ofnitrogen, sulfur and oxygen; and when the heteroaryl ring comprises oneor two nitrogen atoms, a group R⁶ is attached at any nitrogen atom whichallows the substitution.

[0225] It is preferred that D is a thiophene and P is attached to the Dring, giving a skeleton as any of the following:

[0226] It is also preferred that D is pyrrole and P is attached to thenitrogen atom in the D ring, giving a skeleton as any of the following:

[0227] It is also preferred that D is furan and P is attached to the Dring, giving a skeleton as any of the following:

[0228] Another object of the present invention is a compound of thegeneral formula (V)

[0229] wherein P is of the formula (c) as defined in claim 1, R¹, x, y,X, Y, and R³ are as defined in claim 1, and

[0230] wherein D is a five-membered heteroaryl ring, said heteroarylring comprising one or two atoms selected from the group consisting ofnitrogen, sulfur and oxygen; and when the heteroaryl ring comprises oneor two nitrogen atoms, a group R⁶ is attached at any nitrogen atom whichallows the substitution.

[0231] Another object of the present invention is a compound of thegeneral formula (V)

[0232] wherein P is of the formula (a) or (b) as defined in claim 1,preferably wherein R² is H, X, Y, and R³ are as defined in claim 1, and

[0233] wherein D is a five-membered heteroaryl ring, said heteroarylring comprising one or two atoms selected from the group consisting ofnitrogen, sulfur and oxygen; and when the heteroaryl ring comprises oneor two nitrogen atoms, a group R⁶ is attached at any nitrogen atom whichallows the substitution.

[0234] Another object of the present invention is a compound of thegeneral formula (VI)

[0235] wherein P is of the formula (a) or (b) as defined in claim 1,preferably wherein R² is H, X and Y are as defined in claim 1, and R³ isas defined in claim 2.

[0236] Another object of the present invention is a compound of thegeneral formula (VII)

[0237] wherein P is of the formula (a) or (b) as defined in claim 1,preferably wherein R² is H, X and Y are as defined in claim 1, and R³ isas defined in claim 4.

[0238] Another object of the present invention is a compound of thegeneral formula (VIII)

[0239] wherein P is of the formula (a) or (b) as defined in claim 1,preferably wherein R² is H, X, Y, and R³ are as defined in claim 1.

[0240] Another object of the present invention is a compound of thegeneral formula (IX)

[0241] wherein R⁷ in formula (IX) is:

[0242] (a) H,

[0243] (b) C₁₋₆ alkyl,

[0244] (c) benzyl,

[0245] (d) —CH₂—CH₂—OH, or

[0246] (e) CH₂—CH₂—O—CH₃, and

[0247] wherein P is of the formula (a) or (b) as defined in claim 1,preferably wherein R² is H, X, Y, and R³ are as defined in claim 1.

[0248] Another object of the present invention is a compound of thegeneral formula (X)

[0249] wherein P is of the formula (a) or (b) as defined in claim 1,preferably wherein R² is H, X, Y, and R³ are as defined in claim 1.

[0250] Another object of the present invention is a compound of thegeneral formula (XI)

[0251] wherein P is of the formula (a) or (b) as defined in claim 1,preferably wherein R² is H, X and Y are as defined in claim 1, and R³ isas defined in claim 4.

[0252] Another object of the present invention is a compound of thegeneral formula (XII):

[0253] or a pharmaceutically acceptable salt thereof, wherein P and R³are attached to the same ring or to different rings of rings A and B,wherein A, B, Y, P, and R₃ are as defined in claim 1.

[0254] Preferred compounds of the formula (II) are

[0255] 6-Benzenesulfonyl-4-piperazin-1-yl-quinoline hydrochloride;

[0256] 6-[(2-Fluorophenyl)sulfonyl]-4-piperazin-1-ylquinolinehydrochloride;

[0257] 6-(1-Naphthylsulfonyl)-4-piperazin-1-ylquinoline hydrochloride;

[0258] 6-[(3,4-Dichlorophenyl)sulfonyl]-4-piperazin-1-ylquinolinehydrochloride;

[0259] 6-[(3,5-Dimethylphenyl)sulfonyl]-4-piperazin-1-ylquinolinehydrochloride;

[0260] 6-[(2-Chloro-6-methylphenyl)sulfonyl]-4-piperazin-1-ylquinolinehydrochloride;

[0261] 6-[(4-Chlorophenyl)sulfonyl]-4-piperazin-1-ylquinolinehydrochloride;

[0262]6-[(2-Methyl,4-tert-butyl-phenyl)sulfonyl]-4-piperazin-1-ylquinolinehydrochloride;

[0263] 6-[(3,4-Dimethylphenyl)sulfonyl]-4-piperazin-1-ylquinolinehydrochloride;

[0264] 6-[(2,3-Dichlorophenyl)sulfonyl]-4-piperazin-1-ylquinolinehydrochloride;

[0265] 6-[(4-tert-Butylphenyl)sulfonyl]-4-piperazin-1-ylquinolinehydrochloride;

[0266] 6-[(4-Isopropylphenyl)sulfonyl]-4-piperazin-1-ylquinolinehydrochloride;

[0267](4-Piperazin-1-yl-6-{[4-(trifluoromethyl)phenyl]sulfonyl}quinolinehydrochloride;

[0268] 6-[(4-tert-Butylphenyl)sulfonyl]-4-(1,4-diazepan-1-yl)quinolinehydrochloride; and

[0269] 4-(1,4-Diazepan-1-yl)-6-[(4-isopropylphenyl)sulfonyl]quinolinehydrochloride.

[0270] Preferred compounds of the formula (III) are

[0271]7-(2-Chloro-6-methyl-benzenesulfonyl)-1-piperazin-1-yl-isoquinolinehydrochloride;

[0272] 7-(2-t-Butyl-benzenesulfonyl)-1-piperazin-1-yl-isoquinolinehydrochloride;

[0273] 7-(3,4-Dichloro-benzenesulfonyl)-1-piperazin-1-yl-isoquinolinehydrochloride;

[0274] 7-(2,4-Dimethyl-benzenesulfonyl)-1-piperazin-1-yl-isoquinolinehydrochloride;

[0275] 7-(2,5-Dimethyl-benzenesulfonyl)-1-piperazin-1-yl-isoquinolinehydrochloride;

[0276] 7-(p-Chloro-benzenesulfonyl)-1-piperazin-1-yl-isoquinolinehydrochloride;

[0277] 7-Benzenesulfonyl-1-[1,4]diazepan-1-yl-isoquinolinehydrochloride;

[0278]7-(4-tert-Butyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinoline,hydrochloride;

[0279]7-(2-Chloro-6-methyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinolinehydrochloride;

[0280]7-(3,5-Dimethyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinolinehydrochloride;

[0281]7-(3,4-Dichloro-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinolinehydrochloride;

[0282] 7-(4-Chloro-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinolinehydrochloride;

[0283]7-(3,4-Dimethyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinolinehydrochloride;

[0284]7-(2-tert-Butyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinolinehydrochloride;

[0285] 7-Benzenesulfonyl-1-piperazin-yl-isoquinoline hydrochloride; and

[0286] 7-(4-tert-Butyl-benzenesulfonyl-1-piperazin-yl-isoquinolinehydrochloride

[0287] Preferred compounds of the formula (IV) are

[0288] 4-(1,4-Diazepan-1-yl)-2-(phenylsulfonyl)thieno[3,2-c]pyridinehydrochloride;

[0289]4-(1,4-Diazepan-1-yl)-2-[(3,4-dichlorophenyl)sulfonyl]thieno[3,2-c]pyridinehydrochloride;

[0290]4-(1,4-Diazepan-1-yl)-2-[4-tert-butylphenylsulfonyl)thieno[3,2-c]pyridinehydrochloride;

[0291]4-(1,4-Diazepan-1-yl)-2-[4-tert-butylphenylsulfonyl)thieno[3,2-c]pyridinehydrochloride;

[0292]4-(1,4-Diazepan-1-yl)-2-[3,4-dimethylphenylsulfonyl)thieno[3,2-c]pyridinehydrochloride;

[0293]2-[(4-Bromophenyl)sulfonyl]-4-(1,4-diazepan-1-yl)thieno[3,2-c]pyridinehydrochloride;

[0294] 2-(Phenylsulfonyl)-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;

[0295]2-(3-Methoxy-benzenesulfonyl)-4-piperazin-1-yl-thieno[3,2-c]pyridinehydrochloride;

[0296]2-(4-Methoxy-benzenesulfonyl)-4-piperazin-1-yl-thieno[3,2-c]pyridinehydrochloride;

[0297]4-Piperazin-1-yl-2-{[4-trifluoromethyl)phenyl]sulfonyl}thieno[3,2-c]pyridinehydrochloride;

[0298]2-[[2-tert-Butylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;

[0299]2-[(3,4-Dichlorophenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamidehydrochloride;

[0300]2-[(4-tert-Butylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;

[0301] 2-(1-Naphthyl sulfonyl)-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;

[0302]2-[(3-Fluorophenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamidehydrochloride;

[0303] 2-(Mesitylsulfonyl)-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;

[0304]2-[(2-Methoxyphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;

[0305]2-[(2,4-Dimethoxyphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;

[0306]2-[(2,4-Dimethylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;

[0307]2-[(2,5-Dimethylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;

[0308] 2-[(2-Ethylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;

[0309] 4-(Piperazinyl)-2-(3-methoxybenzyl-sulfonyl)-thienopyridinehydrochloride;

[0310] 2-(Benzylsulfonyl)-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;

[0311]4-Piperazin-1-yl-2-{[4-(trifluoromethyl)benzyl]sulfonyl}thieno[3,2-c]pyridinehydrochloride;

[0312] 2-[(3-Bromobenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;

[0313]2-[(2,3-Difluorobenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;

[0314] 2-[(4-Bromobenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;

[0315]2-{[2,5-bis(Trifluoromethyl)benzyl]sulfonyl}-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;

[0316]2-[(4-Methylbenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;

[0317]2-{[5-Chloro-2-(trifluoromethyl)benzyl]sulfonyl}-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;

[0318]2-[(3,5-Dimethoxybenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;

[0319]2-[(2-Naphthylmethyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;

[0320]4-Piperazin-1-yl-2-{[4-(1,2,3-thiadiazol-4-yl)benzyl]sulfonyl}thieno[3,2-c]pyridinehydrochloride;

[0321]1-(4-Pyrrolidin-1-ylphenyl)-2-[(4-piperazine-1-ylthieno[3,2-c]pyridin-2-yl)sulfonyl]ethanonehydrochloride; and

[0322]1-[4-(Diethylamino)phenyl]-2-[(4-piperazine-1-ylthieno[3,2-c]pyridin-2-yl)sulfonyl]ethanonehydrochloride.

[0323] Also preferred compounds of the formula (IV) are

[0324]1-(4-Methylphenylsulphonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridinehydrochloride;

[0325]1-(3-Chloro-2-methylphenylsulphonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridinehydrochloride;

[0326]1-(3,4-Dimethoxyphenylsulphonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridinehydrochloride;

[0327]4-(4-Piperazin-1-yl-pyrrolo[3,2-c]pyridine-1-sulfonyl)-benzonitrilehydrochloride;

[0328]1-(4,5-Dichloro-thiophene-2-sulfonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridinehydrochloride;

[0329]1-(2-Chloro-4-fluorophenylsulphonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridinehydrochloride;

[0330]1-Phenylmethanesulfonyl-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridinehydrochloride;

[0331]1-(5-Chloro-thiophene-2-sulfonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridinehydrochloride;

[0332]1-(4-Butyl-benzenesulfonyl)-4-piperazin-1-yl-1H-pyrrolo(3,2-c)pyridinehydrochloride;

[0333]1-(4-Phenoxy-benzenesulfonyl)-4-piperazin-1-yl-1H-pyrrolo(3,2-c)pyridinehydrochloride;

[0334] 1-(Phenylsulfonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridinehydrochloride;

[0335]1-[(4-Chlorophenyl)sulfonyl]-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridinehydrochloride;

[0336]1-[(4-Methoxyphenyl)sulfonyl]-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridinehydrochloride;

[0337]1-[(2-Methoxy-5-methylphenyl)sulfonyl]-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridinehydrochloride; and

[0338]4-Piperazin-1-yl-1-{[2-(trifluoromethyl)phenyl]sulfonyl}-1H-pyrrolo[3,2-c]pyridinehydrochloride.

[0339] Preferred compounds of the formula (VI) are

[0340]N-(4-Methylphenyl)-4-(4-methylpiperazin-1-yl)thieno[3,2-c]pyridine-2-sulfonamidehydrochloride;

[0341]2-Bromo-4-(4-methyl-piperazin-1-yl)-thieno[3,2-c]pyridine-3-sulfonicacid p-tolylamide hydrochloride;

[0342]4-(4-Methylpiperazin-1-yl)-n-phenylthieno[3,2-c]pyridine-2-sulfonamidehydrochloride;

[0343] 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid(3-fluoro-5-trifluoromethyl-phenyl)amide hydrochloride;

[0344] 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid(4-chloro-phenyl)-amide hydrochloride;

[0345] 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid(4-isopropyl-phenyl)-amide hydrochloride;

[0346] 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acidp-tolylamide hydrochloride;

[0347]4-(4-Methylpiperazin-1-yl)-N-(2-cyclohex-1-en-1-ylethyl)thieno[3,2-c]pyridine-2-sulfonamidehydrochloride;

[0348]2-(4-(4-Methylpiperazin-1-yl)thieno[3,2-c]pyridin-2-ylsulfonyl)-1,2,3,4-tetrahydroisoquinolinehydrochloride;

[0349]4-(4-Methylpiperazin-1-yl)-N-(2-thien-2-ylethyl)thieno[3,2-c]pyridine-2-sulfonamidehydrochloride;

[0350]4-(4-Methylpiperazin-1-yl)-N-[1-(1-naphthyl)ethyl]thieno[3,2-c]pyridine-2-sulfonamidehydrochloride;

[0351]4-(4-Methylpiperazin-1-yl)-N-(4-hexylphenyl)thieno[3,2-c]pyridine-2-sulfonamidehydrochloride;

[0352]N-(3-Chlorobenzyl)-4-(4-methylpiperazin-1-yl)thieno[3,2-c]pyridine-2-sulfonamide;

[0353]4-(4-Methylpiperazin-1-yl)-N-[1-(4-fluorophenyl)ethyl]thieno[3,2-c]pyridine-2-sulfonamidehydrochloride;

[0354]N-(2,3-Difluorobenzyl)-4-(4-methylpiperazin-1-yl)thieno[3,2-c]pyridine-2-sulfonamidehydrochloride;

[0355]4-(4-Methylpiperazin-1-yl)-N-(4-chloro-2,5-dimethoxyphenyl)thieno[3,2-c]pyridine-2-sulfonamidehydrochloride;

[0356]2-Bromo-4-(4-methylpiperazin-1-yl)-N-(2-cyclohex-1-en-1-ylethyl)thieno[3,2-c]pyridine-3-sulfonamidehydrochloride;

[0357]2-Bromo-4-(4-methylpiperazin-1-yl)-N-[(1S)-1-(2-naphthyl)ethyl]thieno[3,2-c]pyridine-3-sulfonamidehydrochloride;

[0358]2-Bromo-4-(4-methylpiperazin-1-yl)-N-[1-(4-fluorophenyl)ethyl]thieno[3,2-c]pyridine-3-sulfonamidehydrochloride;

[0359]2-Bromo-4-(4-methylpiperazin-1-yl)-N-(2,4,5-trimethoxyphenyl)thieno[3,2-c]pyridine-3-sulfonamide;

[0360]N-(3,4-Dichlorophenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamidehydrochloride;

[0361]N-(2,4-Difluorophenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamidehydrochloride;

[0362]4-Piperazin-1-yl-N-[-3-(trifluoromethyl)phenyl]thieno[3,2-c]pyridine-2-sulfonamidehydrochloride;

[0363]N-(3-Ethylphenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamidehydrochloride;

[0364]N-(3,4-Dimethoxyphenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamidehydrochloride;

[0365]N-(4-Bromo-2-methylphenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamidehydrochloride;

[0366]2-(4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonyl)-1,2,3,4-tetrahydro-isoquinolinehydrochloride;

[0367] 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid(2-thiophen-2-yl-ethyl)-amide hydrochloride;

[0368] 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid(4-chloro-2,5-dimethoxy-phenyl)amide hydrochloride;

[0369] 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acidphenethyl-amide hydrochloride;

[0370] 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid(2,6-diethyl-phenyl)-amide hydrochloride;

[0371] 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid(3-phenyl-propyl)-amide hydrochloride;

[0372] 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid(3,3-diphenyl-propyl)-amide hydrochloride;

[0373] 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid[2-(5-methoxy-1H-indol-3-yl)-ethyl]-amide hydrochloride;

[0374] 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid4-trifluoromethyl-benzylamide hydrochloride;

[0375] 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acidbenzyl-ethyl-amide hydrochloride;

[0376]N-(3-Ethylphenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-3-sulfonamidehydrochloride;

[0377]N-(4-Isopropylphenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-3-sulfonamidehydrochloride;

[0378]N-(4-Methylphenyl)-4-(pyrrolidin-3-yloxy)thieno[3,2-c]pyridine-2-sulfonamidehydrochloride;

[0379]N-(4-Methylphenyl)-4-(piperidin-4-yloxy)thieno[3,2-c]pyridine-2-sulfonamidehydrochloride;

[0380]N-(2,3-Difluorobenzyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamidehydrochloride;

[0381]N-(3-Chlorobenzyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamidehydrochloride;

[0382] 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acidphenylamide hydrochloride;

[0383] 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid(4-tert-butyl-phenyl)-amide hydrochloride;

[0384] 4-(4-Methyl-piperazin-1-yl)-thieno[3,2-c]pyridine-2-sulfonic acidphenylamide hydrochloride;

[0385] 4-(4-Methyl-piperazin-1-yl)-thieno[3,2-c]pyridine-2-sulfonic acid(3-chloro-phenyl)-amide hydrochloride;

[0386]2-Bromo-4-(4-methyl-piperazin-1-yl)-thieno[3,2-c]pyridine-3-sulfonicacid phenylamide hydrochloride;

[0387] 4-(4-Methyl-piperazin-1-yl)-thieno[3,2-c]pyridine-3-sulfonic acid(4-methylphenyl)-amide hydrochloride; and

[0388] N-Phenyl-7-piperazin-1-ylthieno[2,3-c]pyridine-2-sulfonamidehydrochloride.

[0389] Preferred compounds of the formula (VII) are

[0390]N-(4-methylphenyl)-4-piperazin-1-ylfuro[3,2-c]pyridine-2-sulfonamidehydrochloride;

[0391] N-phenyl-4-piperazin-1-ylfuro[3,2-c]pyridine-2-sulfonamidehydrochloride; and

[0392] N-phenyl-7-piperazin-1-ylfuro[2,3-c]pyridine-2-sulfonamidehydrochloride.

[0393] A preferred compound of the formula (VIII) is

[0394] 4-Piperazin-1-yl-thiazolo[4,5-c]pyridine-2-sulfonic acidphenylamide hydrochloride.

[0395] Preferred compounds of the formula (IX) are

[0396]N-(4-methylphenyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridine-2-sulfonamidehydrochloride;

[0397] N-phenyl-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridine-2-sulfonamidehydrochloride; and

[0398] N-phenyl-7-piperazin-1-yl-1H-pyrrolo[2,3-c]pyridine-2-sulfonamidehydrochloride.

[0399] Preferred compounds of the formula (X) are

[0400] 4-Chloro-N-[4-(pyrrolidin-3-yloxy)-1-naphthyl]benzenesulfonamidehydrochloride;

[0401] 4-Methoxy-N-[4-(pyrrolidin-3-yloxy)-1-naphthyl]benzenesulfonamidehydrochloride;

[0402]5-Chloro-N-[4-(pyrrolidin-3-yloxy)-1-naphthyl]thiophene-2-sulfonamidehydrochloride;

[0403] 4-Chloro-N-[4-(piperidin-3-yloxy)-1-naphthyl]benzenesulfonamidehydrochloride;

[0404] 4-Methoxy-N-[4-(piperidin-3-yloxy)-1-naphthyl]benzenesulfonamidehydrochloride;

[0405]5-Fluoro-2-methyl-N-[4-(piperidin-4-yloxy)-1-naphthyl]benzenesulfonamidehydrochloride;

[0406]5-Chloro-N-[4-(piperidin-4-yloxy)-1-naphthyl]thiophene-2-sulfonamidehydrochloride;

[0407]4-Chloro-N-{4-[(3S)-pyrrolidin-3-yloxy]-1-naphthyl}benzenesulfonamidehydrochloride; and

[0408]4-Chloro-N-{4-[(3R)-pyrrolidin-3-yloxy]-1-naphthyl}benzenesulfonamidehydrochloride.

[0409] Another object of the present invention is a process for thepreparation of a compound above, said method comprising the steps of:

[0410] (a) Mitsonobu reaction of 4-nitro-1-naphthol with boc-protected3-hydroxypyrrolidine or 4-hydroxypiperidine;

[0411] (b) reduction of the nitro group in the nitronaphthalene obtainedin step (a) to form an aminonaphthalene derivative; and

[0412] (c) synthesis of a sulfonamide by reacting the aminonaphthaleneobtained in step (b) with a suitable sulfonyl chloride.

[0413] Another object of the present invention is a process for thepreparation of a compound above, wherein

[0414] P is

[0415]  said method comprising the steps of:

[0416] preparation of the heteroaromatic 5-member ring fusedhalogen-substituted pyridine, reduction of an aromatic nitro group;aromatic nucleophilic substitution with a thiol via a diazointermediate;oxidation of the thiol derivative to a sulphone; introduction of ahalogen atom by electrophilic aromatic substitution; aromaticnucleophilic substitution of the halogen with a diamine.

[0417] Another object of the present invention is a process for thepreparation of a compound above, wherein

[0418] P is

[0419]  said method comprising the steps of: preparation of theheteroaromatic 5-member ring fused pyridine; introduction of acarboxylic moiety; conversion of the carboxylic moiety to amine byCurtius rearrangement; reaction of the amine group with asulphonylchloride.

[0420] Another object of the present invention is a process for thepreparation of a compound above, wherein

[0421] P is

[0422]  said method comprising the steps of: preparation of theheteroaromatic 5-member ring fused pyridine; introduction ofsulfonylchloride moiety by nucleophilic addition; reaction ofsulphonylchloride moiety with an aniline to obtained a sulfonamide;aromatic nucleophilic substitution of the chloro with a diamine.

[0423] All diastereomeric forms possible (pure enantiomers, tautomers,racemic mixtures and unequal mixtures of two enantiomers) are within thescope of the invention. Such compounds can also occur as cis- or trans-,E- or Z-double bond isomer forms. All isomeric forms are contemplated.

[0424] The compounds of the formulae (I) to (XII) may be used as suchor, where appropriate, as pharmacologically acceptable salts (acid orbase addition salts) thereof.

[0425] The pharmacologically acceptable addition salts as mentionedabove are meant to comprise the therapeutically active non-toxic acidand base addition salt forms that the compounds are able to form.Compounds that have basic properties can be converted to theirpharmaceutically acceptable acid addition salts by treating the baseform with an appropriate acid. Exemplary acids include inorganic acids,such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulphuricacid, phosphoric acid; and organic acids such as acetic acid, propanoicacid, hydroxyacetic acid, lactic acid, pyruvic acid, glycolic acid,maleic acid, malonic acid, oxalic acid, benzenesulphonic acid,toluenesulphonic acid, methanesulphonic acid, trifluoroacetic acid,fumaric acid, succinic acid, malic acid, tartaric acid, citric acid,salicylic acid, p-aminosalicylic acid, pamoic acid, benzoic acid,ascorbic acid and the like. Exemplary base addition salt forms are thesodium, potassium, calcium salts, and salts with pharmaceuticallyacceptable amines such as, for example, ammonia, alkylamines,benzathine, and amino acids, such as, e.g. arginine and lysine. The termaddition salt as used herein also comprises solvates which the compoundsand salts thereof are able to form, such as, for example, hydrates,alcoholates and the like.

[0426] For clinical use, the compounds of the invention are formulatedinto pharmaceutical formulations for oral, rectal, parenteral or othermode of administration. Pharmaceutical formulations are usually preparedby mixing the active substance, or a pharmaceutically acceptable saltthereof, with conventional pharmaceutical excipients. The formulationscan be further prepared by known methods such as granulation,compression, microencapsulation, spray coating, etc. The formulationsmay be prepared by conventional methods in the dosage form of tablets,capsules, granules, powders, syrups, suspensions, suppositories orinjections. Liquid formulations may be prepared by dissolving orsuspending the active substance in water or other suitable vehicles.Tablets and granules may be coated in a conventional manner.

[0427] Another object of the present invention is a compound above foruse in therapy.

[0428] Another object of the present invention is a compound above, andfor the case when rings A and B are both phenyl, P is any one of formula(a) or (c) substituted in position 7 on the naphthalene ring, and R³ issubstituted in position 1 on the naphthalene ring, for use in thetreatment or prophylaxis of a 5-HT₆ receptor related disorder, such asobesity, type II diabetes, and/or disorders of the central nervoussystem, to achieve reduction of body weight and of body weight gain.

[0429] Another object of the present invention is a compound above foruse in the treatment or prophylaxis of disorders of the central nervoussystem.

[0430] Another object of the present invention is a compound above, forthe case when rings A and B are both phenyl, P is any one of formula (a)or (c) substituted in position 7 on the naphthalene ring, and R³ issubstituted in position 1 on the naphthalene ring, and for the case whenring D is a pyrrole ring, P is of the formula (c) and R³ is of theformula

[0431] substituted in position 3 on the pyrrole ring, for use in thetreatment or prophylaxis of type II diabetes.

[0432] Another object of the present invention is a compound above, andfor the case when ring D is a pyrrole ring, P is of the formula (c) andR³ is of the formula

[0433] substituted in position 3 on the pyrrole ring, for use in thetreatment or prophylaxis of obesity, to achieve reduction of body weightand of body weight gain.

[0434] Another object of the present invention is a pharmaceuticalformulation comprising a compound above as an active ingredient, incombination with a pharmaceutically acceptable diluent or carrier.

[0435] Another object of the present invention is a pharmaceuticalformulation comprising a compound above, and for the case when rings Aand B are both phenyl, P is any one of formula (a) or (c) substituted inposition 7 on the naphthalene ring, and R³ is substituted in position 1on the naphthalene ring, as an active ingredient, for use in thetreatment or prophylaxis of a 5-HT₆ receptor related disorder, such asobesity, type II diabetes, and/or disorders of the central nervoussystem, to achieve reduction of body weight and of body weight gain.

[0436] Another object of the present invention is a compound above as anactive ingredient, for use in the treatment or prophylaxis of disordersof the central nervous system.

[0437] Another object of the present invention is a pharmaceuticalformulation comprising a compound above, for the case when rings A and Bare both phenyl, P is any one of formula (a) or (c) substituted inposition 7 on the naphthalene ring, and R³ is substituted in position 1on the naphthalene ring, and for the case when ring D is a pyrrole ring,P is of the formula (c) and R³ is of the formula

[0438] substituted in position 3 on the pyrrole ring, as an activeingredient, for use in the treatment or prophylaxis of type II diabetes.

[0439] Another object of the present invention is a pharmaceuticalformulation comprising a compound above, and for the case when ring D isa pyrrole ring, P is of the formula (c) and R³ is of the formula

[0440] substituted in position 3 on the pyrrole ring, as an activeingredient, for use in the treatment or prophylaxis of obesity, toachieve reduction of body weight and of body weight gain.

[0441] Another object of the present invention is a method for thetreatment or prophylaxis of a 5-HT₆ receptor related disorder, such asobesity, type II diabetes, and/or disorders of the central nervoussystem, to achieve reduction of body weight and of body weight gain,which comprises administering to a subject (e.g., a mammal, a human, ahorse, a dog, or a cat) in need of such treatment an effective amount ofone or more compounds of any of the formulae described above, their saltforms or compositions that include the compounds or their salt forms,and for the case when rings A and B are both phenyl, P is any one offormula (a) or (c) substituted in position 7 on the naphthalene ring,and R³ is substituted in position 1 on the naphthalene ring.

[0442] Another object of the present invention is a method for thetreatment or prophylaxis of disorders of the central nervous system,which comprises administering to a subject in need of such treatment aneffective amount of one or more compounds of any of the formulaedescribed above, their salt forms or compositions that include thecompounds or their salt forms.

[0443] Another object of the present invention is a method for thetreatment or prophylaxis of type II diabetes, which comprisesadministering to a subject in need of such treatment an effective amountof one or more compounds of any of the formulae described above, theirsalt forms or compositions that include the compounds or their saltforms, for the case when rings A and B are both phenyl, P is any one offormula (a) or (c) substituted in position 7 on the naphthalene ring,and R³ is substituted in position 1 on the naphthalene ring, and for thecase when ring D is a pyrrole ring, P is of the formula (c) and R³ is ofthe formula

[0444] substituted in position 3 on the pyrrole ring.

[0445] Another object of the present invention is a method for thetreatment or prophylaxis of obesity, which comprises administering to asubject in need of such treatment an effective amound of one or morecompounds of any of the formulae described above, their salt forms orcompositions that include the compounds or their salt forms, and for thecase when ring D is a pyrrole ring, P is of the formula (c) and R³ is ofthe formula

[0446] substituted in position 3 on the pyrrole ring.

[0447] Another object of the present invention is a method formodulating 5-HT₆ receptor activity, comprising administering to asubject in need thereof an effective amount of one or more compounds ofany of the formulae described above, their salt forms or compositionsthat include the compounds or their salt forms.

[0448] A subject “in need of such treatment” or “in need thereof” caninclude a subject identified as in need of a particular treatment ortreatments. The identification can be in the judgement of a subject or ahealth care professional and can be subjective (e.g., opinion) orobjective (e.g., measurable by a test or a diagnostic method). Themethods delineated herein can also include the step of identifying thatthe subject is in need of treatment of obesity, type II diabetes, ordisorders of the central nervous system.

[0449] Another object of the present invention is the use of one or morecompounds of any of the formulae described above, their salt forms orcompositions that include the compounds or their salt forms, and for thecase when rings A and B are both phenyl, P is any one of formula (a) or(c) substituted in position 7 on the naphthalene ring, and R³ issubstituted in position 1 on the naphthalene ring, for the manufactureof a medicament for use in the treatment or prophylaxis of a 5-HT₆receptor related disorder, such as obesity, type II diabetes, and/ordisorders of the central nervous system, to achieve reduction of bodyweight and of body weight gain.

[0450] Another object of the present invention is the use of one or morecompounds of any of the formulae described above, their salt forms orcompositions that include the compounds or their salt forms for themanufacture of a medicament for use in the treatment or prophylaxis ofdisorders of the central nervous system.

[0451] Another object of the present invention is the use of one or morecompounds of any of the formulae described above, their salt forms orcompositions that include the compounds or their salt forms, for thecase when rings A and B are both phenyl, P is any one of formula (a) or(c) substituted in position 7 on the naphthalene ring, and R³ issubstituted in position 1 on the naphthalene ring, and for the case whenring D is a pyrrole ring, P is of the formula (c) and R³ is of theformula

[0452] substituted in position 3 on the pyrrole ring, for themanufacture of a medicament for use in the treatment or prophylaxis oftype II diabetes.

[0453] Another object of the present invention is the use of one or morecompounds of any of the formulae described above, their salt forms orcompositions that include the compounds or their salt forms, and for thecase when ring D is a pyrrole ring, P is of the formula (c) and R³ is ofthe formula

[0454] substituted in position 3 on the pyrrole ring, for themanufacture of a medicament for use in the treatment or prophylaxis ofobesity, to achieve reduction of body weight and of body weight gain.

[0455] The methods delineated herein can also include the step ofidentifying that the subject is in need of treatment of obesity, type IIdiabetes, or disorders of the central nervous system, or in need ofreducing body weight and of body weight gain.

[0456] The invention further relates to cosmetic use of one or morecompounds of any of the formulae described herein, for causing loss ofweight, as well as cosmetic compositions containing said compounds.

[0457] Still further, the invention relates to a non-therapeutic metodfor impriving the bodily appearance of a mammal, including a human, inwhich the method comprises orally administering to said mammal one ormore compounds of any of the formulae described herein.

[0458] “An effective amount” refers to an amount of a compound thatconfers a therapeutic effect on the treated subject. The therapeuticeffect may be objective (i.e., measurable by some test or marker) orsubjective (i.e., subject gives an indication of or feels an effect).

[0459] For clinical use, the compounds of the invention are formulatedinto pharmaceutical formulations for oral, rectal, parenteral or othermode of administration. Usually the amount of active compounds isbetween 0.1-95% by weight of the preparation, preferably between 0.2-20%by weight in preparations for parenteral use and preferably between 1and 50% by weight in preparations for oral administration.

[0460] The typical daily dose of the active substance varies within awide range and will depend on various factors such as, for example, theindividual requirement of each patient and the route of administration.In general, oral and parenteral dosages will be in the range of 5 to1000 mg per day of active substance, preferably 50 to 150 mg per day.

Processes for Preparation

[0461] In a further aspect the invention relates to methods of makingcompounds of any of the formulae herein comprising reacting any one ormore of the compounds of the formulae delineated herein, including anyprocesses delineated herein. The compounds of the formulae above may beprepared by, or in analogy with, conventional methods, and especiallyaccording to or in analogy with the following methods.

[0462] The chemicals used in the above-described synthetic route mayinclude, for example, solvents, reagents, catalysts, protecting groupand deprotecting group reagents. The methods described above may alsoadditionally include steps, either before or after the steps describedspecifically herein, to add or remove suitable protecting groups inorder to ultimately allow synthesis of the compounds of any of theformulae described above, their salt forms, or compositions that includethe compounds or their salt forms. In addition, various synthetic stepsmay be performed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizingapplicable compounds are known in the art and include, for example,those described in R. Larock, Comprehensive Organic Transformations, VCHPublishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups inOrganic Synthesis, 2^(nd) Ed., John Wiley and Sons (1991); L. Fieser andM. Fieser, Fieser and Fieser 's Reagents for Organic Synthesis, JohnWiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagentsfor Organic Synthesis, John Wiley and Sons (1995) and subsequenteditions thereof.

[0463] The specific examples below are to be construed as merelyillustrative, and not limitative of the remainder of the disclosure inany way whatsoever. Without further elaboration, it is believed that oneskilled in the art can, based on the description herein, utilize thepresent invention to its fullest extent. All publications cited hereinare hereby incorporated by reference in their entirety.

Methods

[0464]¹H nuclear magnetic resonance (NMR) and ¹³C NMR were recorded on aBruker Advance DPX 400 spectrometer at 400.1 and 100.6 MHz,respectively. All spectra were recorded using residual solvent ortetramethylsilane (TMS) as internal standard. IR spectra were recordedon a Perkin-Elmer Spectrum 1000 FT-IR spectrophotometer. Ionspray massspectrometry (MS) spectra were obtained on a Perkin-Elmer API 150EX massspectrometer. Accurate mass measurements were performed on a MicromassLCT dual probe. Preparative HPLC/MS was performed on a Waters/MicromassPlatform ZQ system equipped with System A: ACE 5 C8 column (19×50 mm),eluents: MilliQ water, MeCN and MilliQ/MeCN/0.1%TFA and system B: XterraMS C18, 5 μm column (19×50 mm), eluents: MilliQ water, MeCN and NH₄HCO₃(100 mM). Analytical HPLC were performed on Agilent 1100, column: ACE 3C8 (system A) or column: YMC-Pack (system B), eluents: MilliQ/0.1%TFAand MeCN. Elemental analyses were performed on a Vario E1 instrument.Preparative flash chromatography was performed on Merck silica gel 60(230-400 mesh). TABLE 1

EXAMPLE R⁶ R⁴ 1 6-Benzenesulfonyl-4-piperazin-1-yl-quinolinehydrochloride

2 6-[(2-Fluorophenyl)sulfonyl]-4-piperazin-1-ylquinoline hydrochloride

3 6-(1-Naphthylsulfonyl)-4-piperazin-1-ylquinoline hydrochloride

4 6-[(3,4-Dichlorophenyl)sulfonyl]-4-piperazin-1-ylquinolinehydrochloride

5 6-[(3,5-Dimethylphenyl)sulfonyl]-4-piperazin-1-ylquinolinehydrochloride

6 6-[(2-Chloro-6-methylphenyl)sulfonyl]-4-piperazin-1- ylquinolinehydrochloride

7 6-[(4-Chlorophenyl)sulfonyl]-4-piperazin-1-ylquinoline hydrochloride

8 6-[(2-Methyl,4-tert-butyl-phenyl)sulfonyl]-4-piperazin-1- ylquinolinehydrochloride

9 6-[(3,4-Dimethylphenyl)sulfonyl]-4-piperazin-1-ylquinolinehydrochloride

10 6-[(2,3-Dichlorophenyl)sulfonyl]-4-piperazin-1-ylquinolinehydrochloride

11 6-[(4-tert-Butylphenyl)sulfonyl]-4-piperazin-1-ylquinolinehydrochloride

12 6-[(4-Isopropylphenyl)sulfonyl]-4-piperazin-1-ylquinolinehydrochloride

13 (4-piperazin-1-yl-6-{[4- (trifluoromethyl)phenyl]sulfonyl}quinolinehydrochloride

14 6-[(4-tert-Butylphenyl)sulfonyl]-4-(1,4-diazepan-1-yl)quinolinehydrochloride

15 4-(1,4-Diazepan-1-yl)-6-[(4-isopropylphenyl)sulfonyl]quinolinehydrochloride

[0465]

Methods

[0466] The assigned structures were confirmed by standardspectroscopical methods and elemental analysis and/or high resolutionMS.

[0467] NMR spectra were obtained on Bruker 500 MHz or JEOL 270 MHzspectrometers at 25° C., and the chemical shift values are reported asparts per million (6). MS spectra were acquired on a 2690 SeparationModule (Waters) with a Platform LCZ (Micromass). Flash chromatographywas performed on Silica gel 60 (Merck) or LiChroprep RP-18 (Merck). HPLCanalysis were accomplished on a HP Series1100, with a GROM-SIL 100 ODS-0AB column, 4.6×50 mm. The HPLC purifications were performed onpreparative HPLC/Mass system using YMC Combi prep ODS-AQ column, 56×20mm, Gilson pumps, Dynamax UV-1 detector and Finnigan Mass detector. Theused eluents were H₂O and CH₃CN, both with 0.1% TFA. The purity of thecompounds was determined by HPLC. Elemental analysis was performed atStructural Chemistry Department, Biovitrum AB, Stockholm. Meltingpoints, when given, were obtained on a Büchi or a Gallenkamp meltingpoint apparatus and are uncorrected.

[0468] Intermediate 1

[0469] Synthesis of 6-Amino-quinoline

[0470] A suspension of 6-nitro-quinoline (8.7 g, 5 mmol), palladium oncharcoal (10%) (0.1 g) in methanol (0.2 L) was hydrogenated at roomtemperature for 24 with stirring. The catalyst was filtered and thesolvent evaporated to yield a yellow solid. Crystallisation from ethylacetate yielded the pure title compound as a pale yellow solid (3.3 g,46%). MS m/z: 145 [M+H+].

[0471]¹H NMR (270 MHz, CHCl₃-d) δ ppm 3.89 (s, 2H) 6.87 (d, J=2.64 Hz,1H) 7.14 (dd, J=8.97, 2.64 Hz, 1H) 7.25 (dd, J=8.44, 4.22 Hz, 1H) 7.88(dd, J=7.92, 1.58 Hz, 1H) 7.90 (d, J=8.97 Hz, 1H) 8.63 (dd, J=4.22, 1.58Hz, 1H).

[0472] Intermediate 2

[0473] Synthesis of 6-phenylsulfanyl-quinoline

[0474] A solution of sodium nitrite (1 g, 14 mmol) in water (6 mL) wasslowly added to a stirred solution of 6-amino-quinoline (1.44 g, 10mmol) in sulfuric acid (50%) (8 mL). The temperature was kept below 5°C. during the addition. The reaction mixture was poured into a solutionof potassium hydroxide (9 g, 16 mmol) and thiophenol (1 mL, 9 mmol) inwater (30 mL). The reaction mixture was refluxed for 3 h, cooled andextracted with diethyl ether. The insoluble material was eliminated byfiltration. During filtration most of the material was trapped in thesolid phase. The filtrate was evaporated and the residue was purified bycolumn chromatography (SiO₂, ethyl acetate:hexane, 1:2) to yield acolorless oil (100 mg, 4% PS: the low yield is due to the loss of thematerial during the filtration procedure). MS m/z: 238 [M+H+]. ¹H NMR(270 MHz, CD₃Cl) δ ppm 7.34 (m, 4H) 7.42 (m, 2H) 7.57 (dd, J=8.97, 2.11Hz, 1H) 7.67 (d, J=2.11 Hz, 1H) 7.99 (m, 2H) 8.84 (dd, J=4.22, 1.58 Hz,1H).

[0475] Intermediate 3

[0476] Synthesis of 6-benzenesulfonyl-quinoline 1-oxid

[0477] A solution of m-chloroperbenzoic acid (1 g, 5.8 mmol) in DCM (10mL) was added to a stirred solution of 6-phenylsulfanyl-quinoline (0.25g, 1 mmol) and NaHCO₃ (0.5 g) in DCM (10 mL). The reaction was leftstirring over night, washed with water, NaHCO₃ solution and evaporated.Trituration of the residue in diethyl ether gave the pure title productas a slightly yellow solid (0.14 g, 30%). MS m/z: 287 [M+H+].

[0478] Intermediate 4

[0479] Synthesis of 6-benzenesulfonyl-4-chloro-quinoline

[0480] A solution of 6-benzenesulfonyl-quinoline 1-oxid (135 mg, 0.47mmol) in POCl₃ (4 mL) was heated at 90° C. for 2 h after which thesolution was poured on ice, ammonium hydroxide was added and extractionwith DCM. The organic phase was dried (NaSO₄), the volatiles wereevaporated and the residue was purified by column chromatography (SiO₂,ethyl acetate:petroleum ether, 1:1) to yield a white solid (39 mg, 27%).MS m/z: 305 [M+H+].

EXAMPLE 1

[0481] Synthesis of 6-benzenesulfonyl-4-piperazin-1-yl-quinolineHydrochloride

[0482] A solution of 6-benzenesulfonyl-4-chloro-quinoline (35 mg, 0.11mmol) and piperazine (0.5 g, 2.5 mmol) in acetonitrile (2 mL) was heatedat 80 oc over night. The mixture was extracted with toluene and water.The organic phase was purified by chromatography on silica gel elutedwith CHCl₃ saturated with NH₃ (gas). The pure product was dissolved inethyl acetate and HCl (gas) in diethyl ether was added. The resultingoily residue was dissolved in methanol and ethyl acetate and evaporatedto yield a white solid (24 mg, 77%). MS m/z: 354 [M+H+]. ¹H NMR (270MHz, CH₃OH-D₄) δ ppm 3.52 (m, 4H) 4.13 (m, 4H) 7.36 (d, J=7.18 Hz, 1H)7.57 (m, 3H) 8.01 (m, J=12.25, 8.54 Hz, 3H) 8.28 (d, J=8.91 Hz, 1H) 8.63(d, J=6.68 Hz, 1H) 8.69 (s, 1H).

[0483] Method A

[0484] Preparation of Thiol Derivatives

[0485] tert-Butyl 4-(6-bromoquinolin-4-yl)-1,4-diazepane-1-carboxylate(0.5 g, 1.23 mmol) was mixed with the thiol (1 equiv.), NaOtBu (2equiv.), Pd(PPh₃)₄ (0.05 equiv.) and n-BuOH (5 mL) in a reaction tube.N₂ (g) was flushed through the mixture for 30 minutes. The reactionmixture was heated to 120° C. overnight. The precipitate was filtratedand the reaction mixture concentrated in vacuo. The residue wasdissolved in EtOAc and washed with H₂O, dried (MgSO₄) and evaporated.Purification by flash chromatography using DCM: MeOH 98:2 as eluentafforded the title product that was used in the next step withoutfurther purification.

[0486] Method B

[0487] Oxidation of Thiol Derivatives to Sulphone Derivatives

[0488] The appropriate thiophenols derivatives are dissolved in TFA (5mL) and stirred for 15 minutes at room temperature. H₂O₂ (2 mL) wasadded and the reaction was left stirring overnight. The reactionmixtures are evaporated and the residues are portioned between diethylether and water. The layers are separated and the water layer isextracted with diethyl ether and made basic by adding NaOH 1M.Extraction with DCM, drying with MgSO₄ and evaporation gives the freebases of the products which are dissolved in MeOH, excess of HCl/ether(2M) was added and the solvent evaporated. The residues are purified onpreparative HPLC/MS (Xterra MS C18, 5 m column) using a 10 to 40%MeCN-water gradient (containing 0.1% HOAc) over 10 minutes. The purefractions are pooled and lyophilised. The residues are dissolved in MeOHand treated with excess of HCl/ether (2M). After evaporation of solvent,a solid is obtained and triturated with diethyl ether giving the desiredproducts as HCl-salts.

[0489] Intermediate 5

[0490] tert-Butyl 4-(6-bromoquinolin-4-yl)piperazine-1-carboxylate

[0491] 6-Bromo-4-chloroquinoline (5.0 g, 20.6 mmol),tert-butyl-1-piperazine (4.1 g, 22 mmol), triethylamine (3 mL, 22 mmol)and DMSO (20 mL) were mixed and heated overnight in an oil bath at 100°C. The reaction was cooled and diluted with diethyl ether and washedwith water (5×), dried (MgSO₄) and evaporated. The residue was filteredthrough a short column of silica (2.5-5%) MeOH in CH₂Cl₂ and evaporated.Yield 8.02 g. (97%). Brown liquid. HPLC 98%, R_(T)=3.01 (System A1,10-97% MeCN over 3 min). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.52 (s, 9H)3.12-3.17 (m, 4H) 3.69-3.75 (m, 4H) 6.86 (d, J=5.0 Hz, 1H) 7.72 (dd,J=9.0, 2.26 Hz, 1H) 7.92 (d, J=8.8 Hz, 1H) 8.14 (d, J=2.3 Hz, 1H) 8.73(d, J=5.0 Hz, 1H). MS (ESI+) for C₁₈H₂₂BrN₃O₂ m/z 392.2 (M+H⁺)

EXAMPLE 2

[0492] 6-[(2-Fluorophenyl)sulfonyl]-4-piperazin-1-ylquinolineHydrochloride

[0493] A total amount of 2.25 mmol, of the appropriate thiophenol wasused and the reaction was prolonged with 8 hours. The oxidation step wascompleted after 24 hours at ambient temperature. Purification by columnchromatography on silica gel 10-20% MeOH in DCM gave the free amine thatwas additionally purified by preparative HPLC. Yield 15 mg (4%) Yellowsolid. HPLC 95%, R_(T)=2.33 (System A1, 10-97% MeCN over 3 min). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 3.30-3.42 (m, 4H) 3.51-3.62 (m, 4H) 7.28 (d,J=5.27 Hz, 1H) 7.42 (dd, J=10.29, 8.78 Hz, 1H) 7.52 (t, J=7.28 Hz, 1H)7.77-7.84 (m, 1H) 8.04-8.21 (m, 3H) 8.62 (s, 1H) 8.87 (d, J=5.27 Hz, 1H)9.82 (br s, 2H). MS (ESI+) for C₁₉H₁₈FN₃O₂S m/z 372.0 (M+H⁺). HRMS forC₁₉H₁₈FN₃O₂S: calcd, 371.1104; found, 371.1102.

EXAMPLE 3

[0494] 6-(1-Naphthylsulfonyl)-4-piperazin-1-ylquinoline Hydrochloride

[0495] A total amount of 2.25 mmol, of the appropriate thiophenol wasused and the reaction was prolonged with 8 hours. The oxidation step wascompleted after 24 hours at ambient temperature. Purification by columnchromatography on silica gel 10-20% MeOH in DCM gave the free amine thatwas converted to the HCl-salt. Yield 14 mg (4%). Grey solid. HPLC 95%,R_(T)=2.54 (System A1, 10-97% MeCN over 3 min). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 3.33 (s, 4H) 4.06 (s, 4H) 7.38 (d, J=6.78 Hz, 1H) 7.65(d, J=7.53 Hz, 1H) 7.69-7.75 (m, 1H) 7.82 (t, J=7.78 Hz, 1H) 8.12 (d,J=8.03 Hz, 1H) 8.21-8.30 (m, 2H) 8.38 (d, J=8.03 Hz, 1H) 8.56 (t, J=8.53Hz, 2H) 8.74-8.79 (m, 2H) 10.05 (s, 2H). MS (ESI+) for C₂₃H₂₁N₃O₂S m/z404.4 (M+H⁺) HRMS for C₂₃H₂₁N₃O₂S: calcd, 403.1354; found, 403.1365.

EXAMPLE 4

[0496] 6-[(3,4-Dichlorophenyl)sulfonyl]-4-piperazin-1-ylquinolineHydrochloride

[0497] A total amount of 2.25 mmol, of the appropriate thiophenol wasused and the reaction was prolonged with 8 hours. The oxidation step wascompleted after 24 hours at ambient temperature. Purification by columnchromatography on silica gel 10-20% MeOH in DCM gave the free aminewhich was converted to the HCl-salt giving yellow solid. Yield 15 mg(3%). Yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.35-3.41 (m, 4H)4.06-4.15 (m, 4H) 7.40 (d, J=6.78 Hz, 1H) 7.93 (d, J=8.53 Hz, 1H) 8.04(dd, J=8.53, 2.01 Hz, 1H) 8.27 (d, J=9.03 Hz, 1H) 8.32 (d, J=2.01 Hz,1H) 8.36-8.42 (m, 1H) 8.73 (d, J=1.51 Hz, 1H) 8.82 (d, J=6.53 Hz, 1H)9.86 (s, 2H). MS (ESI+) for C₁₉H₁₇Cl₂ N₃O₂S m/z 422.2 (M+H⁺). HRMS forC₁₉H₁₇Cl₂N₃O₂S: calcd, 421.0419; found, 421.0422. HPLC 95%, R_(T)=20.69(System A1, 10-97% MeCN over 3 min)

EXAMPLE 5

[0498] 6-[(3,5-Dimethylphenyl)sulfonyl]-4-piperazin-1-ylquinolineHydrochloride

[0499] The oxidation step was completed after 2 hours at ambienttemperature. Purification by column chromatography on silica gel 10-20%MeOH in DCM gave the free amine which was converted to the HCl-saltgiving grey solid. Yield 0.007 g (2%). Yellow solid. HPLC 90%,R_(T)=2.57 (System A1, 10-97% MeCN over 3 min). MS (ESI+) forC₂₁H₂₃FN₃O₂S m/z 382.2.

[0500] HRMS for C₂₁H₂₃FN₃O₂S: calcd, 381.1511; found, 381.1521.

EXAMPLE 6

[0501] 6-[(2-Chloro-6-methylphenyl)sulfonyl]-4-piperazin-1-ylquinolineHydrochloride

[0502] A total amount of 2.25 mmol, of the appropriatethiophenol wasused and the reaction was prolonged with 8 hours. Additional H₂O₂ (1 mL)was added and the reaction mixture was stirred at 50° C. for another 48hours. Purification by column chromatography on silica gel 10-20% MeOHin DCM gave the free amine that was converted to the HCl-salt. Yield 33mg (7.5%). White solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.13 (s, 3H)2.98 (s, 4H) 3.72 (s, 4H) 7.06 (d, J=6.78 Hz, 1H) 7.14 (dd, J=11.54,8.03 Hz, 2H) 7.23 (t, J=7.78 Hz, 1H) 7.89 (d, J=8.78 Hz, 1H) 7.94-8.00(m, 1H) 8.24 (s, 1H) 8.45 (d, J=6.78 Hz, 1H) 9.68 (s, 2H). MS (ESI+) forC₂₀H₂₀ClN₃O₂S m/z 402.2 (M+H⁺). HRMS for C₂₀H₂₀ClN₃O₂S: calcd, 401.965;found, 401.967. HPLC 95%, R_(T)=20.55 (System A1, 10-97% MeCN over 3min).

EXAMPLE 7

[0503] 6-[(4-Chlorophenyl)sulfonyl]-4-piperazin-1-ylquinolineHydrochloride

[0504] A total amount of 2.25 mmol, of the appropriate thiophenol wasused and the reaction was prolonged for another 8 hours. The oxidationstep was completed after 24 h at ambient temperature. Purification bycolumn chromatography on silica gel 10-20% MeOH in DCM gave the freeamine that was converted to the HCl-salt. Yield 14 mg (3%). Yellowsolid. HPLC 95%, R_(T)=2.66 (System A1, 10-97% MeCN over 3 min). MS(ESI+) for C₁₉H₁₈ClN₃O₂S m/z 388.2 (M+H⁺). HRMS for C₁₉H₁₈ClN₃O₂S:calcd, 387.0808; found, 387.0821.

EXAMPLE 8

[0505]6-[(2-Methyl,4-tert-butyl-phenyl)sulfonyl]-4-piperazin-1-ylquinolineHydrochloride

[0506] The oxidation step was completed after 2 hours at ambienttemperature. Purification by column chromatography on silica gel 10-20%MeOH in DCM gave the free amine which was converted to the HCl-saltgiving gray solid. Yield 17 mg (4%). HPLC 95%, R_(T)=2.81 (System A1,10-97% MeCN over 3 min). MS (ESI+) for C₂₄H₂₉N₃O₂S m/z 424.2 (M+H⁺).HRMS for C₂₄H₂₉N₃O₂S: calcd, 423.1980; found, 423.1969.

EXAMPLE 9

[0507] 6-[(3,4-Dimethylphenyl)sulfonyl]-4-piperazin-1-ylquinolineHydrochloride

[0508] The oxidation step was completed after 2 hours at ambienttemperature. Purification by column chromatography on silica gel 10-20%MeOH in DCM gave the free amine which was converted to the HCl-salt.Yield 33 mg (8%). Yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.27 (d,J=6.27 Hz, 6H) 3.34 (s, 4H) 4.12 (s, 4H) 7.39 (dd, J=7.40, 2.13 Hz, 2H)7.75 (d, J=7.78 Hz, 1H) 7.81 (s, 1H) 8.32 (s, 2H) 8.61 (s, 1H) 8.78 (d,J=6.78 Hz, 1H) 10.18 (s, 2H). MS (ESI+) for C₂₁H₂₃N₃O₂S m/z 382.2(M+H⁺). HRMS for C₂₁H₂₃N₃O₂S: calcd, 381.1511; found, 381.1519. HPLC95%, R_(T)=2.54 (System A1, 10-97% MeCN over 3 min).

EXAMPLE 10

[0509] 6-[(2,3-Dichlorophenyl)sulfonyl]-4-piperazin-1-ylquinolineHydrochloride

[0510] A total amount of 2.25 mmol, of the appropriate thiophenol wasused and the reaction was prolonged for another 8 hours. The oxidationstep was completed after 24 hours at ambient temperature. Purificationby column chromatography on silica gel 10-20% MeOH in DCM gave the freeamine which was converted to the HCl-salt. Yield 15 mg (3%). Yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.36 (m, 4H) 4.10 (m, 4H) 7.42(d, J=6.78 Hz, 1H) 7.75 (t, J=8.03 Hz, 1H) 8.07 (d, J=8.03 Hz, 1H) 8.24(d, J=9.04 Hz, 1H) 8.33 (dd, J=13.93, 8.41 Hz, 2H) 8.70 (s, 1H) 8.82 (d,J=6.78 Hz, 1H) 10.00 (s, 2H). MS (ESI+) for C₁₉H₁₇Cl₂N₃O₂S m/z 422.2(M+H⁺). HRMS for C₁₉H₁₇Cl₂N₃O₂S: calcd, 421.0419; found, 421.0408. HPLC95%, R_(T)=2.50 (System A1, 10-97% MeCN over 3 min).

EXAMPLE 11

[0511] 6-[(4-tert-Butylphenyl)sulfonyl]-4-piperazin-1-ylquinolineHydrochloride

[0512] tert-Butyl4-{6-[(4-tert-butylphenyl)thio]quinolin-4-yl}piperazine-1-carboxylate(0.60 g, 1.3 mmol) was dissolved in TFA (12 mL) and stirred for 30minutes before H₂O₂ (0.65 mL, 6.3 mmol) was added. The mixture wasstirred for 2 hours and water (5 mL) was added. The mixture wasevaporated and the residue was taken up in water and washed with diethylether (2×). The aqueous phase was adjusted to pH 10 with 1 N NaOH andthe mixture was extracted with CH₂Cl₂ (2×), dried (MgSO₄) andevaporated. The residue was diluted with CH₂Cl₂ and 1.3 mL 2N HCl indiethyl ether was added under vigorous stirring and the mixture wasevaporated and washed with diethyl ether (2×) and dried. Yield: 0.40 g(69%). Grey solid. HPLC 95%, R_(T)=2.77 (System A1, 10-97% MeCN over 3min). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.23 (s, 9H) 3.38 (s, 4H) 4.08 (s,4H) 7.39 (d, J=7.03 Hz, 1H) 7.65 (d, J=8.53 Hz, 2H) 7.96 (d, J=8.53 Hz,2H) 8.25 (d, J=8.78 Hz, 1H) 8.30-8.36 (m, 1H) 8.66 (d, J=1.76 Hz, 1H)8.81 (d, J=7.03 Hz, 1H) 9.85 (br. s, 2H), MS (ESI+) for C₂₃H₂₇N₃O₂S m/z410.4 (M+H⁺).

EXAMPLE 12

[0513] 6-[(4-Isopropylphenyl)sulfonyl]-4-piperazin-1-ylquinolineHydrochloride

[0514] 4-Isopropylthiophenol (0.152 g, 1.0 mmol) was added dropwise to asuspension of tert-butyl4-(6-bromo-quinolin-4-yl)-piperazine-1-carboxylate (0.2 g, 0.51 mmol),Na-t-butoxide (0.192 g, 2.0 mmol) and Pd[P(Ph)₃]₄ (0.030 g, 0.025 mmol)in ethanol (3 mL) at 90° C. and the mixture was stirred for 18 h. Themixture was diluted with THF and filtered through a plug of silica andevaporated. The crude product was dissolved in TFA (5 mL) and stirredfor 15 minutes before 30% H₂O₂ (1 mL) was added. The mixture was stirredfor 2 hours and evaporated. The residue was dissolved in water andwashed with CH₂Cl₂ (2×) and 2 N NaOH was added until pH reached 10 andthe mixture was extracted with CH₂Cl₂ (3×), dried (MgSO₄) andevaporated. The crude product was purified by preparative HPLC 5-95water/acetonitrile collecting on m/z 395.2. After evaporation the freeamine was dissolved in CH₂Cl₂ and and excess of HCl in diethyl ether wasadded and the mixture was evaporated. Yield 0.015 g (7%). ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.17 (d, J=7.03 Hz, 6H) 2.90-3.02 (m, 1H) 3.34-3.42(m, 4H) 4.03-4.12 (m, 4H) 7.39 (d, J=6.78 Hz, 1H) 7.51 (d, J=8.28 Hz,2H) 7.96 (d, J=8.53 Hz, 2H) 8.26 (d, J=9.03 Hz, 1H) 8.29-8.36 (m, 1H)8.66 (s, 1H) 8.80 (d, J=6.78 Hz, 1H) 9.85-9.97 (m, 2H). HPLC 95%,R_(T)=2.65 (System A1, 10-97% MeCN over 3 min).

EXAMPLE 13

[0515] 4-Piperazin-1-yl-6-{[4-(trifluoromethyl)phenyl]sulfonyl}quinolineHydrochloride

[0516] 4-Trifluoromethylthiophenol (0.178 g, 1.0 mmol) was addeddropwise to a suspension of tert-butyl4-(6-bromo-quinolin-4-yl)-piperazine-1-carboxylate (0.2 g, 0.51 mmol),Sodium-t-butoxide (0.192 g, 2.0 mmol) and Pd[P(Ph)₃]₄ (0.030 g, 0.025mmol) in ethanol (3 mL) at 90° C. and the mixture was stirred for 18 h.The mixture was diluted with THF and filtered through a plug of silicaand evaporated. The crude product was dissolved in TFA (5 mL) andstirred for 15 minutes before 30% H₂O₂ (1 mL) was added. The mixture wasstirred for 2 hours and evaporated. The residue was dissolved in waterand washed with CH₂Cl₂ (2×) and 2 N NaOH was added until pH reached 10and the mixture was extracted with CH₂Cl₂ (3×) dried (MgSO₄) andevaporated. The crude was purified by preparative HPLC 5-95water/acetonitrile collecting on m/z 421.1. After evaporation the freeamine was dissolved in CH₂Cl₂ and excess of HCl in diethyl ether wasadded and the mixture was evaporated. Yield 0.024 g (10%). ¹H NMR (400MHz, DMSO-d₆) δ ppm 3.33-3.40 (m, 4H) 4.13-4.21 (m, 4H) 7.42 (d, J=7.03Hz, 1H) 8.02 (d, J=8.53 Hz, 2H) 8.25-8.35 (m, 3H) 8.37-8.53 (m, 1H) 8.76(d, J=1.76 Hz, 1H) 8.80 (d, J=7.03 Hz, 1H) 9.95-10.05 (m, 2H). Yellowoil. HPLC 95%, R_(T)=2.66 (System A1, 10-97% MeCN over 3 min).

[0517] Intermediate 6

[0518] tert-Butyl 4-(6-bromoquinolin-4-yl)-1,4-diazepane-1-carboxylate

[0519] 6-Bromo-4-chloroquinoline (3.5 g, 14.5 mmol) was reacted withtert-butyl 1,4-diazepane-1-carboxylate (3.7 g, 18.8 mmol) and K₂CO₃ (4g, 29 mmol) in DMSO at 100° C. overnight. After cooling the mixture waspoured into water and extracted with DCM. The organic layer was washedwith water, dried (MgSO₄) and evaporated. The residue was purified byflash chromatography using a gradient of EtOAc:hexane 1:1 to 2:1 giving2.1 g (36%) of yellow oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.47 (d, J=5.5Hz, 9H) 2.08-2.16 (m, 2H) 3.35-3.44 (m, 4H) 3.60-3-73 (m, 4H) 6.87 (d,J=5.5 Hz, 1H) 7.69 (dd, J=9.0, 2.0 Hz, 1H) 7.88 (d, J=8.5 Hz, 1H) 8.16(s, 1H) 8.65 (d, J=5.0 Hz, 1H). MS (ESI+) for C₁₉H₂₄BrN₃O₂ m/z 406.4(M+H)⁺. HRMS (EI) calcd for C₁₉H₂₄BrN₃: 405.1052, found 405.1045.

[0520] Intermediate 7

[0521]tert-Butyl-4{3-[(4-tert-butylphenyl)thio]quinolin-5-yl}-1,4-diazepane-1-carboxylate(General Method A)

[0522] The compound was prepared from tert-butyl4-(6-bromoquinolin-4-yl)-1,4-diazepane-1-carboxylate (0.5 g, 1.23 mmol)and p-tert-butylbenzenethiol (0.2 g, 1.23 mmol). Yield: 0.27 g (44%) ofthe title compound. HPLC 89%, R_(T): 3.76 min (5-99% MeCN containing0.1% TFA over 3 min).

[0523] Intermediate 8

[0524]tert-Butyl-4{3-[(4-isopropylphenyl)thio]quinolin-5-yl}-1,4-diazepane-1-carboxylate(General Method A)

[0525] The compound was prepared from tert-butyl4-(6-bromoquinolin-4-yl)-1,4-diazepane-1-carboxylate (0.5 g, 1.23 mmol)and 4-isopropylbenzenethiol (0.19 g, 1.23 mmol). Yield: 0.27 g (46%) ofthe title compound that was used in the next step without furtherpurification. HPLC 89%, R_(T): 3.67 min (5-99% MeCN containing 0.1% TFAover 3 min); MS (ESI+) for C₂₈H₃₅N₃O₂S m/z 478.2 (M+H)⁺.

EXAMPLE 14

[0526] 6-[(4-tert-Butylphenyl)sulfonyl]-4-(1,4-diazepan-1-yl)quinolineHydrochloride (General Method B)

[0527] The compound was synthesized fromtert-butyl-4{3-[(4-tert-butylphenyl)thio]quinolin-5-yl}-1,4-diazepane-1-carboxylate(0.27 g, 0.55 mmol). Yield: 20 mg (8%) of the title compound.; ¹H NMR(270 MHz, DMSO-d₆) δ ppm 1.25 (s, 9H) 2.31 (br s, 2H) 3.25 (br s, 2H)3.49 (br s, 2H) 4.11 br s, 2H) 4.26 (br s, 2H) 7.16 (d, J=7.1 Hz, 1H)7.65 (d, J=8.2 Hz, 2H) 7.94 (d, J=8.2 Hz, 2H) 8.19 (d, J=8.7 Hz, 1H)8.26 (d, J=8.7 1H) 8.62 (d, J=6.3 Hz, 1H) 8.75 (s, 1H) 9.65 (br s, 2H);MS (ESI+) for C₂₄H₂₉N₃O₂S m/z 424.2 (M+H)⁺. HPLC 93%, R_(T): 2.79 min(5-99% MeCN over 3 min).

EXAMPLE 15

[0528] 4-(1,4-Diazepan-1-yl)-6-[(4-isopropylphenyl)sulfonyl]quinolineHydrochloride (General Method B)

[0529] The compound was prepared fromtert-Butyl-4{3-[(4-isopropylphenyl)thio]quinolin-5-yl}-1,4-diazepane-1-carboxylate(0.27 g, 0.57 mmol). Yield: 15 mg (6%) of the title compound.; ¹H NMR(270 MHz, DMSO-d₆) δ ppm 1.16 (d, J=6.9 Hz, 6H) 2.31 (br s, 2H) 2.96 (m,1H) 3.25 (br s, 2H) 3.49 (br s, 2H) 4.11 (br s, 2H) 4.26 (br s, 2H) 7.16(d, J=6.9 Hz, 1H) 7.51 (d, J=8.2 Hz, 2H) 7.94 (d, J=8.2 Hz, 2H) 8.18 (d,J=8.7 Hz, 1H) 8.30 (d, J=8.4 Hz, 1H) 8.62 (d, J=6.1 Hz, 1H) 8.75 (s, 1H)9.62 (br s, 2H); MS (ESI+) for C₂₃H₂₇N₃O₂S m/z 410.4 (M+H)⁺. HPLC 93%,R_(T): 2.70 min (5-99% MeCN over 3 min). TABLE 2

EXAMPLE R⁷ R¹ 16 7-(2-Chloro-6-methyl-benzenesulfonyl)-1-piperazin-1-yl-isoquinoline hydrochloride

17 7-(2-t-Butyl-benzenesulfonyl)-1-piperazin-1-yl-isoquinolinehydrochloride

18 7-(3,4-Dichloro-benzenesulfonyl)-1-piperazin-1-yl-isoquinolinehydrochloride

19 7-(3,4-Dimethyl-benzenesulfonyl)-1-piperazin-1-yl-isoquinolinehydrochloride

20 7-(2,5-Dimethyl-benzenesulfonyl)-1-piperazin-1-yl-isoquinolinehydrochloride

21 7-(p-Chloro-benzenesulfonyl)-1-piperazin-1-yl-isoquinolinehydrochloride

22 7-Benzenesulfonyl-1-[1,4]diazepan-1-yl-isoquinolin, hydrochloride

23 7-(4-tert-Butyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]- isoquinoline,hydrochloride

24 7-(2-Chloro-6-methyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinoline hydrochloride

25 7-(3,5-Dimethyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]- isoquinolinehydrochloride

26 7-(3,4-Dichloro-benzenesulfonyl)-1-[1,4]diazepan-1-yl]- isoquinolinehydrochloride

27 7-(4-Chloro-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinolinehydrochloride

28 7-(3,4-Dimethyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]- isoquinolinehydrochloride

29 7-(2-tert-Butyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]- isoquinolinehydrochloride

30 7-Benzenesulfonyl-1-piperazin-yl-isoquinoline hydrochloride

31 7-(4-tert-Butyl-benzenesulfonyl-1-piperazin-yl-isoquinolinehydrochloride

[0530]

[0531] Intermediate 9

[0532] 7-Bromo-1-Chloroisoquinoline

[0533] To phosphorus oxychloride (46.6 mL, 0.5 mol) at room temperaturewas added, portionwise, 7-bromo-1-hydroxyisoquinoline (11.2 g, 0.05mol). The mixture was heated to 100° C. for 90 min with rapid stirring.On cooling to room temperature, the mixture was poured, cautiously ontoice/water (200 mL). Dropwise addition of aqueous ammonia raised the pH=8and the resulting precipitate was collected by filtration, washing withcold water. The solid was dried under reduced vacuum at 45° C. for 12 h.13.86 g (115%) Beige solid isolated. ¹H NMR (DMSO-d₆) δ 8.4 (s, 1H),8.34-8.38 (d, J=6 Hz, 1H), 8.03-8.07 (m, 2H), 7.91-7.96 (d, J=6 Hz, 1H);HPLC: 96%; LCMS: 242, 244, 246.

[0534] Nucleophilic Displacement of Chlorine

[0535] Intermediate 10

[0536] 4-(7-Bromo-isoquinoline-1-yl)-piperazine-1-carboxylic Acid,tert-butyl Ester

[0537] To a suspension of 7-bromo-1-chloroisoquinoline (3.14 g, 13 mmol)in DMSO (20 mL) at room temperature was added either carboxylic acidtert-butyl (BOC)piperazine (7.23 g, 38.8 mmol) or BOC-homopiperazine(7.77 g, 38.8 mmol) and then potassium carbonate (5.36 g, 39 mmol). Themixture was heated to 110° C. for 24 h. On cooling, the mixture waspoured onto ice/water (50 mL) and extracted with ethyl acetate (3×50mL). The combined organic phases were washed with water 50 mL) and brine(50 mL). Before drying over anhydrous sodium sulfate. Removal of solventunder reduced pressure gave crude product. Purification was performed byapplying the crude material to a plug of silica in a filter funnel andeluting with heptane/ethyl acetate (2:1) and gave 2.73 g (54%) yellowoil. ¹H NMR (CDCl₃) δ 8.20-8.22 (m, 1H), 8.13-8.18 (d, J=6 Hz, 1H),7.65-7-71 (dd, J=12, 3 Hz, 1H), 7.59-7.65 (d, J=12 Hz, 1H), 7.21-7.25(m, 1H), 3.64-3.73 (m, 4H), 7.27-7.36 (m, 4H), 1.49 (s, 9H); LCMS: 392,394, 395.

[0538] Intermediate 11

[0539] 4-(7-Bromo-isoquinoline-1-yl)-[1,4]diazepane-1-carboxylic Acid,tert-butyl Ester

[0540] 2.75 g (52%) yellow oil isolated ¹H NMR (CDCl₃) δ 8.19-8.24 (m,1H), 8.06-8.12 (d, J=9 Hz, 1H), 7.54-7.68 (m, 2H), 7.11 (m, 1H),3.47-3.74 (m, 8H), 1.98-2.16 (m, 2H), 1.48 (s, 9H); LCMS: 406, 407, 408.

[0541] Palladium-Catalysed Aryl Thiol Coupling

[0542] To 7-bromo-1-chloroisoquinoline (1 mmol) in butan-1-ol (20 mL) atroom temperature was added sodium tert-butoxide (481 mg, 5 mmol), thiol(1.5 mmol) and tetrakis triphenylphosphine palladium (60 mg, catalytic).The mixture was heated to 120° C. for 16 h. On cooling to roomtemperature, the mixture was filtered through silica eluting with THF.Removal of solvent under reduced pressure gave the crude product whichwas used without further purification in the subsequent step.

[0543] Intermediate 12

[0544]4-[7-(2-Chloro-6-methyl-phenylsulfanyl)-isoquinolin-1-yl]-piperazine-1-carboxylicAcid tert-butyl Ester

[0545] A mixture of4-(7-bromo-isoquinoline-1-yl)-piperazine-1-carboxylic acid, tert-butylester (0.5 g, 1.3 mmol), 2-chloro-6-methyl-thiophenol (0.206 g, 1.3mmol), NatBuO (0.44 g, 4.5 mmol), Pd(PPh₃)₄ (74 mg, 0.065 mmol) in nBuOH(10 mL) was heated at 110° C., 3 h. The reaction mixture was filtered.The filtrate was concentrated and the residue was dissolved in ethylacetate. The organic phase was washed with water (50 mL×3), separatedand dried (MgSO₄), filtered. The volatiles were evaporated and theresidue was purified by flash column chromatography (SiO₂, n-heptane:ethyl acetate 8:2) to give 530 mg of the title compound as colourlessoil (yield 86.4%). ¹H NMR (CDCl₃) δ 8.05 (d, 1H), 7.65 (d, 1H),7.20-7.45 (m, 5H), 7.15 (d, 1H), 3.26-3.40 (m, 4H), 3.10-3.20 (m, 4H),2.5 (s, 3H), 1.38 (s, 9H).

[0546] Intermediate 13

[0547]4-[7-(2-t-butyl-phenylsulfanyl)-isoquinolin-1-yl]-piperazine-1-carboxylicAcid tert-butyl Ester

[0548] A mixture of4-(7-bromo-isoquinoline-1-yl)-piperazine-1-carboxylic acid, tert-butylester (0.5 g, 1.3 mmol), 2-t-butyl-thiophenol (0.216 g, 1.3 mmol),Nat-BuO (0.44 g, 4.5 mmol), Pd(PPh₃)₄ (74 mg, 0.065 mmol) in n-BuOH (10mL) was heated at 110° C., 3 h. The reaction mixture was filtered. Thefiltrate was concentrated and the residue was dissolved in ethylacetate. The organic phase was washed with water (50 mL×3), separatedand dried (MgSO₄), filtered. The volatiles were evaporated and theresidue was purified by flash column chromatography (SiO₂, n-heptane:ethyl acetate 8:2) to give 440 mg of the title compound as colorless oil(yield 71%). ¹H NMR (CDCl₃) δ 8.00-8.10 (m, 2H), 7.15-7.65 (m, 7H),3.60-3.70 (m, 1H), 3.30-3.45 (m, 4H), 3.05-3.20 (m, 3H), 1.55 (s, 9H),1.50 (s, 9H).

[0549] Intermediate 14

[0550]4-[7-(3,4-Dichloro-phenylsulfanyl)-isoquinolin-1-yl]-piperazine-1-carboxylicAcid tert-butyl Ester

[0551] A mixture of4-(7-bromo-isoquinoline-1-yl)-piperazine-1-carboxylic acid, tert-butylester (0.5 g, 1.3 mmol), 3,4-dichloro-thiophenol (165 uL, 1.3 mmol),NatBuO (0.44 g, 4.5 mmol), Pd(PPh₃)₄ (74 mg, 0.065 mmol) in n-BuOH (10mL) was heated at 110° C., 3 h. The reaction mixture was filtered. Thefiltrate was concentrated and the residue was dissolved in ethylacetate. The organic phase was washed with water (50 mL×3), separatedand dried (MgSO₄), filtered. The volatiles were evaporated and theresidue was purified by flash column chromatography (SiO₂,n-pentane:ethyl acetate 9.5:0.5→8:2) to give 230 mg of the titlecompound as colorless oil (yield 36%). ¹H NMR (CDCl₃) δ 8.10-8.20 (m,2H), 7.90 (bs, 1H), 7.65-7.75 (m, 2H), 7.10-7.55 (m, 3H), 3.50-3.65 (m,4H), 3.20-3.30 (m, 4H), 1.50 (s, 9H).

[0552] Intermediate 15

[0553]4-[7-(3,4-Dimethyl-phenylsulfanyl)-isoquinolin-1-yl]-piperazine-1-carboxylicAcid tert-butyl Ester

[0554] A mixture of4-(7-bromo-isoquinoline-1-yl)-piperazine-1-carboxylic acid, tert-butylester (0.5 g, 1.3 mmol), 3,4-dimethyl-thiophenol (175 uL, 1.3 mmol),NatBuO (0.44 g, 4.5 mmol), Pd(PPh₃)₄ (74 mg, 0.065 mmol) in n-BuOH (10mL) was heated at 110° C., 3 h. The reaction mixture was filtered. Thefiltrate was concentrated and the residue was dissolved in ethylacetate. The organic phase was washed with water (50 mL×3), separatedand dried (MgSO₄), filtered. The volatiles were evaporated and theresidue was purified by flash column chromatography (SiO₂,n-pentane:ethyl acetate 9.5:0.5→8:2) to give 260 mg of the titlecompound as colorless oil (yield 44%). ¹H NMR (CDCl₃) δ 8.00-8.10 (m,2H), 7.55-7.65 (m, 3H), 7.40-7.50 (m, 1H), 7.10-7.30 (m, 2H), 3.30-3.40(m, 4H), 3.10-3.20 (m, 4H), 2.30 (s, 3H), 2.25 (s, 3H), 1.50 (s, 9H).

[0555] Intermediate 16

[0556]4-[7-(3,5-Dimethyl-phenylsulfanyl)-isoquinolin-1-yl]-piperazine-1-carboxylicAcid tert-butyl Ester

[0557] A mixture of4-(7-bromo-isoquinoline-1-yl)-piperazine-1-carboxylic acid, tert-butylester (0.5 g, 1.3 mmol), 3,5-dimethyl-thiophenol (180 mg, 1.3 mmol),NatBuO (0.44 g, 4.5 mmol), Pd(PPh₃)₄ (74 mg, 0.065 mmol) in nBuOH (10mL) was heated at 110° C., 3 h. The reaction mixture was filtered. Thefiltrate was concentrated and the residue was dissolved in ethylacetate. The organic phase was washed with water (50 mL×3), separatedand dried (MgSO₄), filtered. The volatiles were evaporated and theresidue was purified by flash column chromatography (SiO₂,n-pentane:ethyl acetate 9.8:0.2→8:2) to give 380 mg of the titlecompound as colourless oil (yield 65%). ¹H NMR (CDCl₃) δ 8.05-8.10 (m,1H), 7.80-7.85 (m. 1H), 7.60-7.75 (m, 1H), 7.17-7.25 (m, 1H), 7.10 (bs,2H), 7.00 (bs, 1H), 3.40-3.50 (m, 4H), 3.10-3.20 (m, 4H), 2.25 (bs, 6H),1.50 (s, 9H).

[0558] Intermediate 17

[0559]4-[7-(p-Chloro-phenylsulfanyl)-isoquinolin-1-yl]-piperazine-1-carboxylicAcid tert-butyl Ester

[0560] A mixture of4-(7-bromo-isoquinoline-1-yl)-piperazine-1-carboxylic acid, tert-butylester (0.5 g, 1.3 mmol), p-chloro-thiophenol (188 mg, 1.3 mmol), NatBuO(0.44 g, 4.5 mmol), Pd(PPh₃)₄ (74 mg, 0.065 mmol) in nBuOH (10 mL) washeated at 110° C., 3 h. The reaction mixture was filtered. The filtratewas concentrated and the residue was dissolved in ethyl acetate. Theorganic phase was washed with water (50 mL×3), separated and dried(MgSO₄), filtered. The volatiles were evaporated and the residue waspurified by flash column chromatography (SiO₂, n-pentane:ethyl acetate9.5:0.5→8:2) to give 300 mg of the title compound as colourless oil(yield 50%). ¹H NMR (CDCl₃) δ 8.05-8.15 (m, 2H), 7.60-7.70 (m, 2H),7.40-7.50 (m, 2H), 7.15-7.30 (m, 3H), 3.45-3.55 (m, 4H), 3.10-3.15 (m,4H), 1.50 (s, 9H).

[0561] Intermediate 18

[0562] 4-(7-Phenylsulfanyl-isoquinoline-1-yl)-piperazine-1-carboxylicAcid, tert-butyl Ester

[0563] LCMS: 422, 423.

[0564] Intermediate 19

[0565]4-[7-(4-tert-Butyl-phenylsulfanyl)-isoquinoline-1-yl]-piperazine-1-carboxylicAcid, tert-butyl Ester

[0566] LCMS: 478, 479.

[0567] Intermediate 20

[0568]4-(7-Phenylsulfanyl-isoquinoline-1-yl)-[1,4]diazepane-1-carboxylic Acid,tert-butyl Ester

[0569] MS: 368, 369, 370.

[0570] Intermediate 21

[0571]4-[7-(4-tert-Butyl-phenylsulfanyl)-isoquinoline-1-yl]-[1,4]diazepane-1-carboxylicAcid, tert-butyl Ester

[0572] MS: 424, 425, 426.

[0573] Intermediate 22

[0574]4-[7-(2-Chloro-6-methyl-phenylsulfanyl)-isoquinoline-1-yl]-[1,4]diazepane-1-carboxylicAcid, tert-butyl Ester

[0575] MS: 416, 417, 418.

[0576] Intermediate 23

[0577]4-[7-(3,4-Dimethyl-phenylsulfanyl)-isoquinoline-1-yl]-[1,4]diazepane-1-carboxylicAcid, tert-butyl Ester

[0578] MS: 396, 397, 398.

[0579] Intermediate 24

[0580]4-[7-(3,4-Dichloro-phenylsulfanyl)-isoquinoline-1-yl]-[1,4]diazepane-1-carboxylicAcid, tert-butyl Ester

[0581] MS: 436, 437, 438.

[0582] Intermediate 25

[0583]4-[7-(4-Chloro-phenylsulfanyl)-isoquinoline-1-yl]-[1,4]diazepane-1-carboxylicAcid, tert-butyl Ester

[0584] MS: 402, 404.

[0585] Intermediate 26

[0586]4-[7-(3,4-Dimethyl-phenylsulfanyl)-isoquinoline-1-yl]-[1,4]diazepane-1-carboxylicAcid, tert-butyl Ester

[0587] LCMS: 464, 465, 466.

[0588] Intermediate 27

[0589]4-[7-(2-tert-Butyl-phenylsulfanyl)-isoquinoline-1-yl]-[1,4]diazepane-1-carboxylicAcid, tert-butyl Ester

[0590] LCMS: 492, 493, 494.

[0591] BOC Deprotection and Oxidation of Thiols to Sulphone Derivatives

[0592] Each thiol (0.2-1.14 mmol) was dissolved in trifluoroacetic acid(1.5 mL) at 0° C. and stirred for 15 mins at this temperature. To thiswas added 33% aqueous hydrogen peroxide solution (5-100 mL). Theresulting mixture was stirred at room temperature for 90 min and thentreated with sodium hydroxide solution (1M, 25 mL). Extraction of thismixture with ethyl acetate (3×50 mL) was followed by the washing of thecombined organic layers with brine (50 mL). The organic extracts weredried over anhydrous sodium sulfate and then the solvent was removedunder reduced pressure. The crude product was purified by preparativeLCMS. Treatment of the purified material with HCl/Ether (1M, 1 mL) gavethe final product as a white solid.

EXAMPLE 16

[0593]7-(2-Chloro-6-methyl-benzenesulfonyl)-1-piperazin-1-yl-isoquinolineHydrochloride

[0594] A mixture of4-[7-(2-chloro-6-methyl-phenylsulfanyl)-isoquinolin-1-yl]-piperazine-1-carboxylicacid tert-butyl ester (160 mg, 0.340 mmol), H₂O₂ (30% in water, 200 uL),trifluoroacetic acid (2 mL) was heated at 50° C., 2 h. A water solutionof NaOH (1N) was added (pH=14), ethyl acetate was added and the organicphase was separated, dried (MgSO₄), filtered. The filtrated wasconcentrated and the residue was purified by flash column chromatography(SiO₂, dichloromethane:methanol 8:2) to lead to 77 mg of the productcompound as free base (yield 56%). The free base was converted intohydrochloride by treatment with HCl in diethyl ether. ¹H NMR (CH₃OH-d₄)δ 8.88 (bs, 1H), 8.05-8.20 (m. 3H), 7.65 (d, 1H), 7.35-7.55 (m, 3H),3.85-3.95 (m, 4H), 3.00-3.15 (m, 4H), 2.95 (s, 3H).

EXAMPLE 17

[0595] 7-(2-t-Butyl-benzenesulfonyl)-1-piperazin-1-yl-isoquinolineHydrochloride

[0596] A mixture of4-[7-(2-tbutyl-phenylsulfanyl)-isoquinolin-1-yl]-piperazine-1-carboxylicacid tert-butyl ester (273 mg, 0.571 mmol), H₂O₂ (30% in water, 1 mL),trifluoroacetic acid (3 mL) was heated at 50° C., 2 h. The reaction wascontinued overnight at 35° C. A water solution of NaOH (1N) was added(pH=14), ethyl acetate was added and the organic phase was separated,dried (MgSO₄), filtered. The filtrated was concentrated and the residuewas purified by flash column chromatography (SiO₂,dichloromethane:methanol 8:2) to lead to 50 mg of the title compound asfree base (yield 56%). The free base was converted into hydrochloride bytreatment with HCl in diethyl ether. ¹H NMR (CH₃OH-d₄) δ 8.55 (d, 1H),8.25 (d, 1H), 7.95-8.10 (m, 3H), 7.55 (d, 1H), 7.55-7.65 (m, 2H), 7.4(d, 1H), 3.60-3.75 (m, 4H), 3.40-3.50 (m, 4H), 1.55 (s, 9H).

EXAMPLE 18

[0597] 7-(3,4-Dichloro-benzenesulfonyl)-1-piperazin-1-yl-isoquinolineHydrochloride

[0598] A mixture of4-[7-(3,4-dichloro-phenylsulfanyl)-isoquinolin-1-yl]-piperazine-1-carboxylicacid tert-butyl ester (230 mg, 0.47 mmol), H₂O₂ (30% in water, 0.5 mL),trifluoroacetic acid (1.5 mL) was heated at 50° C., 2 h. The reactionwas continued overnight at 35° C. A water solution of NaOH (1N) wasadded (pH=14), ethyl acetate was added and the organic phase wasseparated, dried (MgSO₄), filtered. The filtrated was concentrated andthe residue was purified by flash column chromatography (SiO₂,dichloromethane:methanol 9:1) The free base was converted intohydrochloride by treatment with HCl in diethyl ether to obtained 45 mgof the title compound. ¹H NMR (CH₃OH-d₄) δ 8.75-8.85 (m, 1H), 8.10-8.30(m, 4H), 7.90-8.00 (m, 1H), 7.75-7.85 (m, 1H), 7.50-7.60 (m, 1H),3.85-3.90 (m, 4H), 3.50-3.70 (m, 4H).

EXAMPLE 19

[0599] 7-(3,4-Dimethyl-benzenesulfonyl)-1-piperazin-1-yl-isoquinolineHydrochloride

[0600] A mixture of4-[7-(3,4-dimethyl-phenylsulfanyl)-isoquinolin-1-yl]-piperazine-1-carboxylicacid tert-butyl ester (260 mg, 0.58 mmol), H₂O₂ (30% in water, 0.5 mL),trifluoroacetic acid (1.5 mL) was heated at 50° C., 2 h. The reactionwas continued overnight at 35° C. A water solution of NaOH (1N) wasadded (pH=14), ethyl acetate was added and the organic phase wasseparated, dried (MgSO₄), filtered. The filtrated was concentrated andthe residue was purified by flash column chromatography (SiO₂,dichloromethane:methanol 9:1) The free base was converted intohydrochloride by treatment with HCl in diethyl ether to obtained 20 mgof the title compound. ¹H NMR (CH₃OH-d₄) δ 8.75-8.80 (m, 1H), 8.10-8.25(m, 3H), 7.70-7.85 (m, 2H), 7.60-7.70 (m, 1H), 7.35-7.40 (m, 1H),3.90-4.00 (m, 4H), 3.55-3.65 (m, 4H), 2.35 (bs, 6H).

EXAMPLE 20

[0601] 7-(2,5-Dimethyl-benzenesulfonyl)-1-piperazin-1-yl-isoquinolineHydrochloride

[0602] A mixture of4-[7-(2,5-dimethyl-phenylsulfanyl)-isoquinolin-1-yl]-piperazine-1-carboxylicacid tert-butyl ester (380 mg, 0.846 mmol), H₂O₂ (30% in water, 0.5 mL),trifluoroacetic acid (3 mL) was heated at 50° C., 2 h. The reaction wascontinued overnight at 35° C. A water solution of NaOH (1N) was added(pH=14), ethyl acetate was added and the organic phase was separated,dried (MgSO₄), filtered. The filtrated was concentrated and the residuewas purified by flash column chromatography (SiO₂,dichloromethane:methanol 9.8:0.2→9.5:0.5) The free base was convertedinto hydrochloride by treatment with HCl in diethyl ether to obtained120 mg of the title compound. ¹H NMR (CH₃OH-d₄) δ 8.75-8.80 (m, 1H),8.25-8.30 (m, 1H), 8.05-8.20 (m, 2H), 7.60-7.70 (m, 3H), 7.30-7.35 (m,1H), 4.00-4.10 (m, 4H), 3.60-3.70 (m, 4H), 2.30-1.35 (bs, 6H).

EXAMPLE 21

[0603] 7-(p-Chloro-benzenesulfonyl)-1-piperazin-1-yl-isoquinolineHydrochloride

[0604] A mixture of4-[7-(p-chloro-phenylsulfanyl)-isoquinolin-1-yl]-piperazine-1-carboxylicacid tert-butyl ester (297 mg, 0.65 mmol), H₂O₂ (30% in water, 0.5 mL),trifluoroacetic acid (3 mL) was heated at 50° C., 2 h. The reaction wascontinued overnight at 35° C. A water solution of NaOH (1N) was added(pH=14), ethyl acetate was added and the organic phase was separated,dried (MgSO₄), filtered. The filtrated was concentrated and the residuewas purified by flash column chromatography (SiO₂,dichloromethane:methanol 9.5:0.5→9.0:1.0) The free base was convertedinto hydrochloride by treatment with HCl in diethyl ether to obtained 70mg of the title compound. ¹H NMR (CH₃OH-d₄) δ 8.75-8.85 (m, 2H),8.10-8.25 (m, 3H), 8.00-8.08 (m, 2H), 7.60-7.68 (m, 3H), 3.85-3.95 (m,4H), 3.55-3.65 (m, 4H).

EXAMPLE 22

[0605] 7-Benzenesulfonyl-1-[1,4]diazepan-1-yl-isoquinoline Hydrochloride

[0606] 30 mg. ¹H NMR (DMSO-d₆) δ 9.3 (s, 1H), 8.58 (s, 1H), 8.26-8.30(d, J=9 Hz, 1H), 8.1-8.13 (m, 2H), 8.01-8.06 (d, J=6 Hz, 1H), 7.6-7.76(m, 3H), 7.53-7.58 (d, J=6 Hz, 1H), 3.70-3.90 (m, 4H) 3.58-3.66 (m, 2H),3.29-3.40 (m, 2H); LCMS: 368, 369 HPLC: 98%.

EXAMPLE 23

[0607]7-(4-tert-Butyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinolineHydrochloride

[0608] Isolated 69 mg. ¹H NMR (DMSO-d₆) δ 9.2 (s, 1H), 8.65 (s, 1H),8.09-8.15 (d, J=6 Hz, 1H), 8.03-8.08 (d, J=15 Hz, 1H), 7.89-7.96 (d, J=9Hz, 2H), 7.60-7.67 (d, J=9 Hz, 2H), 7.33-7.38 (d, J=9 Hz, 1H), 4.01-4.09(m, 2H), 3.83-3.91 (m, 2H), 3.43-3.52 (m, 2H), 3.23-3.33 (m, 2H), 1.25(s, 9H); LCMS: 424, 425, HPLC: 97%.

EXAMPLE 24

[0609]7-(2-Chloro-6-methyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinolineHydrochloride

[0610] Isolated 27 mg ¹H NMR (DMSO-d₆) δ 8.81 (s, 1H), 8.28 (m, 1H),8.10-8.18 (d, J=6 Hz, 1H), 7.94-8.08 (m, 2H), 7.45-7.62 (m, 3H),7.36-7.42 (d, J=6 Hz, 1H), 3.75-3.86 (m, 2H), 3.41-3.51 (m, 2H),3.18-3.32 (m, 2H), 2.86 (s, 3H), 2.14-2.19(m 2H); LCMS: 416, 418 HPLC:98%.

EXAMPLE 25

[0611]7-(3,5-Dimethyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinolineHydrochloride

[0612] Isolated 62 mg. ¹H NMR (DMSO-d₆) δ 9.35 (s, 1H), 8.67 (m, 1H),8.00-8.18 (m, 3H), 7.58-7.69 (m, 2H), 7.45-7.41 (d, J=6 Hz, 1H),7.30-7.35 (m, 1H), 4.06-4.14 (m, 2H), 3.86-3.97 (m, 2H), 3.42-3.52 (m,2H), 3.23-3.31 (m, 2H), 2.33 (s, 6H) 2.23-2.25 (m 2H); LCMS: 436, 438,HPLC: 95%.

EXAMPLE 26

[0613]7-(3,4-Dichloro-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinoline,Hydrochloride

[0614] Isolated 11 mg. ¹H NMR (CD₃OD) δ 8.88 (m, 1H), 8.23-8.29 (d, J=12Hz, 1H), 8.13-8.16 (d, J=3 Hz, 1H), 8.04-8.10 (d, J=9 Hz, 1H), 7.88-7.94(d, J=9 Hz, 1H), 7.79-7.84 (d, J=6 Hz, 1H), 7.67-7.73 (d, J=9 Hz, 1H),7.42-7.46 (d, J=6 Hz, 1H), 4.28-4.35 (m, 2H), 4.09-4.16 (m, 2H),3.69-3.75 (m, 2H), 2.33-2.46 (m, 2H); LCMS: 368, 369; HPLC: 97%.

EXAMPLE 27

[0615] 7-(4-Chloro-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinoline,Hydrochloride Isolated

[0616] 41 mg. ¹H NMR (DMSO-d₆) δ 9.27 (s, 1H), 8.68 (m, 1H), 7.99-8.17(m, 5H), 7.66-7.75 (d, J=9 Hz, 2H), 7.33-7.39 (d, J=6 Hz, 1H), 4.03-4.11(m, 2H), 3.83-3.93 (m, 2H), 3.43-3.53 (m, 2H), 3.23-3.32 (m, 2H),2.19-2.30 (m, 2H); LCMS: 402, 404; HPLC: 98%.

EXAMPLE 28

[0617]7-(3,4-Dimethyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinoline,Hydrochloride

[0618] Isolated 10 mg. ¹H NMR (DMSO-d₆) δ 9.41 (s, 1H), 8.67 (s, 1H),8.00-8.16 (m, 3H), 7.76-7.82 (m, 1H), 7.68-7.77 (d, J=9 Hz, 1H),7.32-7.42 (d, J=9 Hz, 2H), 3.99-4.40 (m, 4H), 3.49 (m, 2H), 3.33 (m,2H), 2.29 (s, 3H), 2.25 (s, 3H); LCMS: 396, 397; HPLC: 92%.

EXAMPLE 29

[0619]7-(2-tert-Butyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinoline,Hydrochloride

[0620] Isolated 5 mg. ¹H NMR (DMSO-d₆) δ 9.27 (s, 1H), 8.52 (s, 1H),8.06-8.16 (m, 2H), 7.97-7.97 (m, 2H), 7.72-7.78 (m, 1H), 7.61-7.70 (m,1H), 7.40-7.45 (d, J=9 Hz, 2H), 3.69-3.99 (m, 4H), 3.43 (s, 2H), 3.25(s, 2H), 2.05-2.26(m, 2H); 1.52 (s, 9H); LCMS: 424, 425; HPLC: 90%.

EXAMPLE 30

[0621] 7-Benzenesulfonyl-1-piperazin-yl-isoquinoline, Hydrochloride

[0622] Isolated 10 mg. ¹H NMR (DMSO-d₆) δ 9.04 (s, 1H), 8.65 (s, 1H),8.12-8.16 (d, J=6 Hz, 1H), 7.98-8.05 (m, 5H), 7.58-7.72 (m, 2H),7.32-7.36 (d, J=6 Hz, 1H), 3.98-4.04 (m, 4H), 3.80-3.86 (m, 4H); LCMS:354, 355; HPLC: 98%.

EXAMPLE 31

[0623] 7-(4-tert-Butyl-benzenesulfonyl-1-piperazin-yl-isoquinoline,Hydrochloride

[0624] Isolated 10 mg. ¹H NMR (DMSO-d₆) δ 9.33 (s, 1H), 8.57 (s, 1H),8.24-8.29 (d, J=9 Hz, 1H), 8.11 (m, 2H), 7.91-7.97 (d, J=9 Hz, 2H),7.60-7.66 (d, J=12 Hz, 2H), 7.52-7.57 (d, J=6 Hz, 1H), 3.59-3.68 (m,4H), 3.29-3.40 (m, 4H), 1.24 (s, 9H); LCMS: 410, 411 HPLC: 90 TABLE 3

EXAMPLE NAME R¹ R³ 32 4-Chloro-N-[4-(pyrrolidin-3-yloxy)-1-naphthyl]benzenesulfonamide hydrochloride

33 4-Methoxy-N-[4-(pyrrolidin-3-yloxy)-1- naphthyl]benzenesulfonamidehydrochloride

34 5-Chloro-N-[4-(pyrrolidin-3-yloxy)-1-naphthyl]thiophene-2-sulfonamide hydrochloride

35 4-Chloro-N-[4-(piperidin-3-yloxy)-1- naphthyl]benzenesulfonamidehydrochloride

26 4-Methoxy-N-[4-(piperidin-3-yloxy)-1- naphthyl]benzenesulfonamidehydrochloride

37 5-Fluoro-2-methyl-N-[4-(piperidin-4-yloxy)-1-naphthyl]benzenesulfonamide hydrochloride

38 5-Chloro-N-[4-(piperidin-4-yloxy)-1- naphthyl]thiophene-2-sulfonamidehydrochloride

39 4-Chloro-N-{4-[(3S)-pyrrolidin-3-yloxy]-1-naphthyl}benzenesulfonamide hydrochloride

40 4-Chloro-N-{4-[(3R)-pyrrolidin-3-yloxy]-1-naphthyl}benzenesulfonamide hydrochloride

[0625]

[0626] General Method C

[0627] Mitsonobu reaction of 4-nitro-1-naphthol with boc-protected3-hydroxypyrrolidine and 4-hydroxypiperidine 4-Nitro-1-naphthol (1equiv.) was dissolved in THF (3 mL/mmol), tert-butyl3-hydroxypyrrolidine-1-carboxylate (2 equiv.) was added followed by PPh₃(2 equiv.). The solution was kept under N₂-atmosphere and cooled withice-bath. Diethylazodicarboxylate (DEAD; 2 equiv.) was added dropwise.The ice-bath was removed after 10 min and the reaction mixture wasstirred at ambient temperature overnight. The solvent was evaporated andthe residue was re-dissolved in EtOAc. The formed precipitate wascollected by filtration. The solution was concentrated in vacuo andpurified by flash chromatography (SiO₂, EtOAc:iso-hexane 2:8→EtOAc)

[0628] General Method D

[0629] Reduction of Nitronaphthalene Derivatives

[0630] To a solution of corresponding nitronaphthalenes (1 equiv.)(prepared by General method A) in MeOH (2 mL/mmol), was added Pd/C (10%)and the reaction mixture was stirred overnight under hydrogen (1 atm).The reaction mixture was filtered and the filtrate was concentrated invacuo to give corresponding aminonaphthalene derivatives.

[0631] General Method E

[0632] Reaction of Aminonaphthalene Derivatives with Sulfonyl Chlorides

[0633] To a solution of the aminonaphthalene derivatives (1 equiv.) inCH₂Cl₂ (8 mL/mmol) was added pyridine (3 equiv.) followed by thecorresponding sulfonyl chloride (1.2 equiv.). The mixtures were stirredat ambient temperature overnight, washed with HCl (1M) (2 mL) and dried(MgSO₄). The volatiles were eliminated under vacuo and gave the crudeproduct which were purified by flash chromatography (SiO₂,EtOAc:iso-hexane 1:4) to give desired sulfonamide.

[0634] General Method F

[0635] Deprotection of Boc-Group

[0636] The sulfonamide derivatives (prepared by General Method C) weredissolved in a small amount of MeOH and treated with an excess of HCl indiethyl ether (1M). Stirring at ambient temperature overnight resultedin a precipitate which were collected by filtration giving the titlecompounds as its hydrochloride salts.

[0637] General Method G

[0638] 3-Hydroxypyrrolidine (1 equiv.) was dissolved in MeOH (1 mL/mmol)and cooled on ice-bath. (BOC)₂O (1.1 equiv.) was added and the mixturewas stirred for 2 h at ambient temperature. Pyridine/water (10/10 mL)was added and the mixture was stirred overnight. Evaporation of solventsand co-evaporation with toluene provided the desired boc-protected3-hydroxypyrrolidine.

[0639] Intermediate 28

[0640] tert-Butyl 3-[(4-nitro-1-naphthyl)oxy]pyrrolidine-1-carboxylate(General Method C)

[0641] The crude product was purified by colum chromatography. Thecompound was prepared from 4-nitro-1-naphthol (2.85 g, 15.1 mmol). Thematerial thus obtained was dissolved in small amount of EtOAc andiso-hexane was added. The formed solid was collected by filtration andtriturated with MeOH to give the pure title compound 4.6 g (85%). HPLC99%, R_(T)=2.70 (System A1, 10-97% MeCN over 3 min). ¹H NMR (400 MHz,CDCl₃) δ ppm 1.46 (d, J=7.03 Hz, 9H) 2.26-2.38 (m, 2H) 3.60-3.81 (m, 4H)5.20 (br s, 1H) 6.76 (d, J=8.53 Hz, 1H) 7.58 (t, J=7.53 Hz, 1H) 7.73 (t,J=7.53 Hz, 1H) 8.34 (dd, J=20.33, 8.78 Hz, 2H) 8.75 (d, J=9.04 Hz, 1H).MS (ESI+) for C₁₉H₂₂N₂O₅ m/z 376.2 (M+NH)⁺, 359.2 (M+H)⁺, 303.2(M−tBu)⁺. HPLC 99%, R_(T)=2.78 min (System B1, 10-90% MeCN over 3 min).

[0642] Intermediate 29

[0643] tert-Butyl 3-[(4-amino-1-naphthyl)oxy]pyrrolidine-1-carboxylate(General Method D)

[0644] The compound was prepared from intermediate 1 (2.6 g, 7.2 mmol),Yield: 2.1 g (87%) of the title compound as purple solid. HPLC 96%,R_(T)=1.768 min (System A1, 10-97% MeCN over 3 min). HPLC 95%,R_(T)=1.6⁰⁴ min (System B1, 10-90% MeCN over 3 min). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.37 (d, J=22.59 Hz, 9H) 2.12 (s, 2H) 3.43-3.46 (m, 4H)4.96 (s, 1H) 5.50 (s, 2H) 6.63 (d, J=8.03 Hz, 1H) 6.81 (d, J=8.03 Hz,1H) 7.41 (dd, J=6.02, 3.01 Hz, 2H) 7.94-8.01 (m, 2H). MS (ESI+) forC₁₉H₂₄N₂O₃ m/z 329.2 (M+H)⁺, 273.2 (M−tBu)⁺, 229.2 (M−Boc)⁺.

[0645] Intermediate 30

[0646] tert-Butyl3-[(4-{[4-chlorophenyl)sulfonyl]amino}-1-naphthyl)oxy]pyrrolidine-1-carboxylate(General Method E)

[0647] The compound was prepared from intermediate 2 (0.2 g, 0.61 mmol).The crude material was triturated with CH₃CN to give 0.14 g (46%) of thetitle compound as a pale pink solid. HPLC 97%, R_(T)=2.703 min (SystemA1, 10-97% MeCN over 3 min). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.46 (d,J=4.02 Hz, 9H) 2.18-2.30 (m, 2H) 3.54-3.76 (m, 4H) 5.05 (br s, 1H)6.62-6.65 (m, 1H) 6.74-6.76 (m, 1H) 7.17-7.23 (m, 1H) 7.32 (d, J=9.04Hz, 2H) 7.39-7.45 (m, 2H) 7.62 (d, J=8.53 Hz, 2H) 7.68-7.72 (m, 1H)8.16-8.19 (m, 1H). MS (ESI+) for C₂₅H₂₇ClN₂O₅S m/z 520.2 (M+NH₄)⁺, 447.0(M−tBu)⁺. HPLC 98%, R_(T)=2.738 min (System B1, 10-90% MeCN over 3 min).

[0648] Intermediate 31

[0649] tert-Butyl3-[(4-{[(4-methoxyphenyl)sulfonyl]amino}-1-naphthyl)oxy]pyrrolidine-1-carboxylate(General Method E)

[0650] The compound was prepared from intermediate 2 (0.2 g, 0.61 mmol),Yield: 0.2 g (66%) of the title compound as a pink oil. HPLC 98%,R_(T)=2.617 min (System A1, 10-97% MeCN over 3 min). ¹H NMR (400 MHz,CDCl₃) δ ppm 1.45 (d, J=5.02 Hz, 9H) 2.14-2.31 (m, 2H) 3.54-3.76 (m, 4H)3.79 (s, 3H) 5.04 (br s, 1H) 6.60-6.65 (m, 2H) 6.81 (d, J=8.53 Hz, 2H)7.15-7.24 (m, 1H) 7.38-7.44 (m, 2H) 7.60-7.64 (m, 2H) 7.71-7.76 (m, 1H)8.14-8.18 (m, 1H). MS (ESI+) for C₂₆H₃₀N₂O₆S m/z 516.4 (M+NH₄)⁺, 443.0(M−tBu)⁺, 399.2 (M−Boc)⁺.

[0651] Intermediate 32

[0652] tert-Butyl3-[(4-{[(5-chloro-2-thienyl)sulfonyl]amino}-1-naphthyl)oxy]pyrrolidine-1-carboxylate(General Method E)

[0653] The compound was prepared from intermediate 2 (0.2 g, 0.61 mmol),Yield: 0.21 g (68%) of the title compound as a yellow solid. HPLC 99%,R_(T)=2.777 min (System B1, 10-90% MeCN over 3 min). ¹H NMR (400 MHz,CDCl₃) δ ppm 1.46 (d, J=6.02 Hz, 9H) 2.16-2.30 (m, 2H) 3.55-3.74 (m, 4H)5.07 (br s, 1H) 6.67-6.70 (m, 1H) 6.75 (d, J=4.02 Hz, 1H) 6.77 (br s,1H) 7.13 (br s, 1H) 7.28-7.35 (m, 1H) 7.46-7.48 (m, 2H) 7.75-7.79 (m,1H) 8.19-8.22 (m, 1H). MS (ESI+) for C₂₃H₂₅ClN₂O₅S₂ m/z 526.2 (M+NH₄)⁺,453.0 (M−tBu)⁺, 409.2 (M−Boc)⁺. HPLC 99%, R_(T)=2.767 min (System A1,10-97% MeCN over 3 min).

[0654] Intermediate 33

[0655] tert-Butyl 4-[(4-nitro-1-naphthyl)oxy]piperidine-1-carboxylate(General Method C)

[0656] The compound was prepared from 4-nitro-1-naphthol (2 g, 10.6mmol). The material obtained after flash chromatography was not pureaccording to NMR. Recrystallization from EtOAc/iso-hexane gave 2.3 g(62%) of the title compound as a yellow solid. HPLC 98%, R_(T)=2.842 min(System A1, 10-97% MeCN over 3 min ¹H NMR (400 MHz, CDCl₃) δ ppm 1.48(s, 9H) 1.99 (m, 4H) 3.54 (m, 2H) 3.70 (m, 2H) 4.87 (m, 1H) 6.82 (d,J=9.04 Hz, 1H) 7.59 (m, 1H) 7.74 (m, 1H) 8.38 (d, J=8.53 Hz, 2H) 8.77(d, J=8.53 Hz, 1H). MS (ESI+) for C₂₀H₂₄N₂O₅ m/z 373.0 (M+H)⁺, 390.2(M+NH₄)⁺, 317.0 (M−tBu)⁺. HPLC 98%, R_(T)=2.973 min (System B1, 10-90%MeCN over 3 min).

[0657] Intermediate 34

[0658] tert-Butyl 4-[(4-amino-1-naphthyl)oxy]piperidine-1-carboxylate(General Method C)

[0659] The compound was prepared from intermediate 6 (2.3 g, 7.0 mmol),Yield: 2 g (95%) as pink oil. HPLC 94%, R_(T)=2.885 min (System B1,10-90% MeCN over 3 min). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.46 (s, 9H)1.80-1.98 (m, 4H) 3.35-3.41 (m, 2H) 3.46 (s, 3H) 3.69-3.75 (m, 2H) 3.88(br s, 1H) 4.50-4.54 (m, 1H) 7.45-7.50 (m, 2H) 7.79-7.81 (m, 1H)8.22-8.24 (m, 1H). MS (ESI+) for C₂₀H₂₆N₂O₃ m/z 343.2 (M+H)⁺. HPLC 94%,R_(T)=2.735 min (System A1, 10-97% MeCN over 3 min).

[0660] Intermediate 35

[0661] tert-Butyl4-[(4-{[(4-chlorophenyl)sulfonyl]amino}-1-naphthyl)oxy]piperidine-1-carboxylate(General Method E)

[0662] The compound was prepared from intermediate 7 (0.25 g, 0.73mmol), Yield: 0.29 g (77%). HPLC 98%, R_(T)=2.906 min (System A1, 10-97%MeCN over 3 min). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.47 (s, 9H) 1.88 (m,2H) 1.98 (m, 2H) 3.47 (m, 2H) 3.68 (m, 2H) 4.69 (m, 1H) 6.61 (s, 1H)6.70 (d, J=8.03 Hz, 1H) 7.17 (d, J=8.03 Hz, 1H) 7.32 (m, 2H) 7.43 (m,2H) 7.62 (m, 2H) 7.70 (m, 1H). MS (ESI+) for C₂₆H₂₉ClN₂O₅S m/z 534.0(M+NH₄)⁺, 461.2 (M−tBu)⁺. HPLC 98%, R_(T)=2.843 min (System B1, 10-90%MeCN over 3 min).

[0663] Intermediate 36

[0664] tert-Butyl4-[(4-{[(4-methoxyphenyl)sulfonyl]amino}-1-naphthyl)oxy]piperidine-1-carboxylate(General Method E)

[0665] The compound was prepared from intermediate 7 (0.25 g, 0.73mmol). Yield: 0.21 g (56%) of the title compound as pink solid. HPLC100%, R_(T)=2.755 min (System A1, 10-97% MeCN over 3 min). ¹H NMR (400MHz, CDCl₃) δ ppm 1.47 (s, 9H) 1.86-2.01 (m, 4H) 3.43-3.49 (m, 2H)3.65-3.71 (m, 2H) 3.79 (s, 3H) 4.65-4.70 (m, 1H) 6.58 (s, 1H) 6.69 (d,J=8.53 Hz, 1H) 6.83-6.79 (m, 2H) 7.17 (d, J=8.03 Hz, 1H) 7.39-7.44 (m,2H) 7.61-7.64 (m, 2H) 7.75-7.77 (m, 1H) 8.21-8.24 (m, 1H). MS (ESI+) forC₂₇H₃₂N₂O₆S m/z 530.2 (M+NH₄)⁺, 457.2 (M−tBu)⁺, 413.4 (M−Boc)⁺. HPLC99%, R_(T)=2.668 min (System B1, 10-90% MeCN over 3 min).

[0666] Intermediate 37

[0667] tert-Butyl4-[(4-{[(5-fluoro-2-methylphenyl)sulfonyl]amino}-1-naphthyl)oxy]piperidine-1-carboxylate(General Method E)

[0668] The compound was prepared from tert-butyl4-[(4-amino-1-naphthyl)oxy]piperidine-1-carboxylate (0.25 g, 0.73 mmol).Yield: 0.24 g (64%) of the title compound as a pink solid. HPLC 99%,R_(T)=2.809 min (System B1, 10-90% MeCN over 3 min). ¹H NMR (400 MHz,CDCl₃) δ ppm 1.46 (s, 9H) 1.83-1.98 (m, 4H) 2.54 (s, 3H) 3.42-3.48 (m,2H) 3.63-3.69 (m, 2H) 4.64-4.68 (m, 1H) 6.64-6.68 (m, 2H) 7.03 (d,J=8.53 Hz, 1H) 7.10 (m, 1H) 7.22 (dd, J=8.53, 5.02 Hz, 1H) 7.44-7.48 (m,2H) 7.55 (dd, J=8.53, 2.51 Hz, 1H) 7.83-7.86 (m, 1H) 8.24 (m, 1H). MS(ESI+) for C₂₇H₃₁FN₂O₅S m/z 532.2 (M+NH₄)⁺, 459.2 (M−tBu)⁺, 415.2(M−Boc)⁺. HPLC 100%, R_(T)=2.877 min (System A1, 10-97% MeCN over 3min).

[0669] Intermediate 38

[0670] tert-Butyl4-[(4-{[(5-chloro-2-thienyl)sulfonyl]amino}-1-naphthyl)oxy]piperidine-1-carboxylate(General Method E)

[0671] The compound was prepared from tert-butyl4-[(4-amino-1-naphthyl)oxy]piperidine-1-carboxylate (0.25 g, 0.73 mmol).Yield: 0.25 g (65%) of the title compound as a pink solid. HPLC 98%,R_(T)=2.8²⁷ min (System B1, 10-90% MeCN over 3 min). ¹H NMR (400 MHz,CDCl₃) δ ppm 1.47 (s, 9H) 1.86-2.03 (m, 4H) 3.45-3.51 (m, 2H) 3.66-3.72(m, 2H) 4.69-4.74 (m, 1H) 6.66 (s, 1H) 6.74-6.76 (m, 2H) 7.14 (d, J=4.02Hz, 1H) 7.30 (d, J=8.03 Hz, 1H) 7.45-7.50 (m, 2H) 7.76-7.79 (m, 1H)8.25-8.28 (m, 1H) MS (ESI+) for C₂₄H₂₇ClN₂O₅S₂ m/z 540.4 (M+NH₄)⁺, 467.2(M−tBu)⁺. HPLC 99%, R_(T)=2.910 min (System A1, 10-97% MeCN over 3 min).

[0672] Intermediate 39

[0673] tert-Butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (GeneralMethod G)

[0674] The compound was prepared from (3R)-3-hydroxypyrrolidine (5 g,57.4 mmol). Yield: 9.6 g (90%) of the title compound. ¹H NMR (400 MHz,CDCl₃) δ ppm 1.43 (s, 9H) 1.90-1.98 (m, 2H) 3.27-3.47 (m, 4H) 4.40 (brs, 1H).

[0675] Intermediate 40

[0676] tert-Butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (GeneralMethod G)

[0677] The compound was prepared from (3S)-3-hydroxypyrrolidine (5 g,57.4 mmol). Yield: 8 g (86%) of the title compound. ¹H NMR (400 MHz,CDCl₃) δ ppm 1.40 (s, 9H) 1.86-1.91 (m, 2H) 3.24-3.42 (m, 4H) 4.36 (brs, 1H).

[0678] Intermediate 41

[0679] tert-Butyl(3S)-3-[(4-nitro-1-naphthyl)oxy]pyrrolidine-1-carboxylate (GeneralMethod C)

[0680] The compound was prepared from tert-butyl(3R)-3-hydroxypyrrolidine-1-carboxylate (3.56 g, 19 mmol) and4-nitro-1-naphthol (3 g, 15.9 mmol). Yield: 5 g (88%) of the titlecompound as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.45 (d, J=7.03Hz, 9H) 2.22-2.38 (m, 2H) 3.54-3.83 (m, 4H) 5.18 (br s, 1H) 6.74 (d,J=8.53 Hz, 1H) 7.56 (t, J=7.78 Hz, 1H) 7.71 (t, J=7.78 Hz, 1H) 8.29 (d,J=8.53 Hz, 1H) 8.33 (d, J=8.53 Hz, 1H) 8.72 (d, J=8.53 Hz, 1H). MS(ESI+) for C₁₉H₂₂N₂O₅ m/z 376.2 (M+NH₄)⁺, 303.2 (M−tBu)⁺. HPLC 100%,R_(T)=2.768 min (System A1, 10-97% MeCN over 3 min).

[0681] Intermediate 42

[0682] tert-Butyl(3R)-3-[(4-nitro-1-naphthyl)oxy]pyrrolidine-1-carboxylate (GeneralMethod C)

[0683] The compound was prepared from tert-butyl(3S)-3-hydroxypyrrolidine-1-carboxylate (3.56 g, 19 mmol) and4-nitro-1-naphthol (3 g, 15.9 mmol). Yield: 2.8 g (49%) of the titlecompound as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.46 (d, J=7.03Hz, 9H) 2.26-2.38 (m, 2H) 3.55-3.81 (m, 4H) 5.20 (br s, 1H) 6.77 (d,J=8.53 Hz, 1H) 7.59 (t, J=7.53 Hz, 1H) 7.72-7.76 (m, 1H) 8.32 (d, J=8.03Hz, 1H) 8.37 (d, J=8.53 Hz, 1H) 8.76 (d, J=8.53 Hz, 1H). HPLC 95%,R_(T)=2.775 min (System A1, 10-97% MeCN over 3 min).

[0684] Intermediate 43

[0685] tert-Butyl(3S)-3-[(4-amino-1-naphthyl)oxy]pyrrolidine-1-carboxylate (GeneralMethod D)

[0686] The compound was prepared from tert-butyl(3S)-3-[(4-nitro-1-naphthyl)oxy]pyrrolidine-1-carboxylate (5 g, 14mmol). Yield: 3.5 g (76%) of the title compound as dark pink solid. ¹HNMR (400 MHz, CDCl₃) δ ppm 1.46 (d, J=14.56 Hz, 9H) 2.08-2.13 (m, 1H)2.27-2.30 (m, J=13.05 Hz, 1H) 3.54-3.77 (m, 4H) 3.88 (br s, 2H) 4.96 (brs, 1H) 6.65-6.70 (m, 2H) 7.45-7.51 (m, 2H) 7.79-7.81 (m, 1H) 8.15-8.19(m, 1H). MS (ESI+) for C₁₉H₂₄N₂O₃ m/z 329.2 (M+H)⁺, 273.2 (M−tBu)⁺,229.2 (M−Boc)⁺. HPLC 95%, R_(T)=1.854 min (System A1, 10-97% MeCN over 3min).

[0687] Intermediate 44

[0688] tert-Butyl(3R)-3-[(4-amino-1-naphthyl)oxy]pyrrolidine-1-carboxylate (GeneralMethod D)

[0689] The compound was prepared from tert-butyl(3R)-3-[(4-nitro-1-naphthyl)oxy]pyrrolidine-1-carboxylate (2.8 g, 7.8mmol). Yield: 1.8 g (72%) of the title compound as dark pink solid. ¹HNMR (400 MHz, CDCl₃) δ ppm 1.46 (d, J=14.56 Hz, 9H) 2.07-2.14 (m, 1H)2.27-2.30 (m, 1H) 3.54-3.77 (m, 4H) 3.93 (br s, 2H) 4.96 (br s, 1H)6.65-6.70 (m, 2H) 7.45-7.51 (m, 2H) 7.79-7.81 (m, 1H) 8.16-8.18 (m, 1H).MS (ESI+) for C₁₉H₂₄N₂O₃ m/z 329.2 (M+H)⁺, 273.2 (M−tBu)⁺, 229.2(M−Boc)⁺. HPLC 94%, R_(T)=1.751 min (System A1, 10-97% MeCN over 3 min).

[0690] Intermediate 45

[0691] tert-Butyl(3S)-3-[(4-{[(4-chlorophenyl)sulfonyl]amino}-1-naphthyl)oxy]pyrrolidine-1-carboxylate(General Method E)

[0692] The compound was prepared from tert-butyl(3S)-3-[(4-nitro-1-naphthyl)oxy]pyrrolidine-1-carboxylate (0.3 g, 0.9mmol) and 4-chloro-phenylsulfonylchloride (0.23 g, 1.1 mmol). Yield:0.23 g (50%) of the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.46(d, J=4.52 Hz, 9H) 2.15-2-34 (m, 2H) 3.54-3.74 (m, 4H) 5.05 (br s, 1H)6.62-6.71 (m, 2H) 7.17-7.23 (m, 1H) 7.33 (d, J=8.53 Hz, 1H) 7.39-7.43(m, 2H) 7.62-7.64 (m, 2H) 7.65-7.70 (m, J=6.02 Hz, 1H) 8.18 (d, J=8.53Hz, 1H) MS (ESI+) for C₂₅H₂₇ClN₂O₅S m/z 520.2 (M+NH₄)⁺, 447.0 (M−tBu)⁺.HPLC 100%, R_(T)=2.772 min (System A1, 10-97% MeCN over 3 min).

[0693] Intermediate 46

[0694] tert-Butyl(3R)-3-[(4-{[(4-chlorophenyl)sulfonyl]amino}-1-naphthyl)oxy]pyrrolidine-1-carboxylate(General Method E)

[0695] The compound was prepared from tert-butyl(3R)-3-[(4-nitro-1-naphthyl)oxy]pyrrolidine-1-carboxylate (0.3 g, 0.9mmol) and 4-chloro-phenylsulfonylchloride (0.23 g, 1.1 mmol). Yield: 0.4g (87%) of the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.46 (d,J=4.52 Hz, 9H) 2.15-2-34 (m, 2H) 3.54-3.74 (m, 4H) 5.05 (br s, 1H)6.60-6.66 (m, 2H) 7.17-7.23 (m, 1H) 7.33 (d, J=8.53 Hz, 1H) 7.39-7.43(m, 2H) 7.62-7.64 (m, 2H) 7.65-7.70 (m, J=6.02 Hz, 1H) 8.18 (d, J=8.53Hz, 1H) MS (ESI+) for C₂₅H₂₇ClN₂O₅S m/z 520.2 (M+NH₄)⁺, 447.0 (M−tBu)⁺.HPLC 100%, R_(T)=2.769 min (System A1, 10-97% MeCN over 3 min).

EXAMPLE 32

[0696] 4-Chloro-N-[4-(pyrrolidin-3-yloxy)-1-naphthyl]benzenesulfonamideHydrochloride (General Method F)

[0697] The compound was prepared from intermediate 3 (0.13 g, 0.26mmol). The solid was further purified by trituration with diethyl ethergiving 0.11 g (95%) of the title compound as white solid. HPLC 98%,R_(T)=1.810 min (System A1, 10-97% MeCN over 3 min). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.21-2.26 (m, 2H) 3.32-3.37 (m, 2H) 3.48-3.50 (m, 2H)5.28 (br s, 1H) 6.91-6.98 (m, 2H) 7.44-7.50 (m, 2H) 7.56-7.64 (m, 4H)7.88-7.90 (m, 1H) 8.20-8.23 (m, 1H). MS (ESI+) for C₂₀H₁₉ClN₂O₃S m/z401.2 (M+H)⁺. HPLC 98%, R_(T)=1.651 min (System B1, 10-90% MeCN over 3min).

EXAMPLE 33

[0698] 4-Methoxy-N-[4-(pyrrolidin-3-yloxy)-1-naphthyl]benzenesulfonamideHydrochloride (General Method F)

[0699] The compound was prepared from intermediate 4 (0.18 g, 0.36mmol), Yield: 0.12 g (76%) of the title compound as a white solid. HPLC100%, R_(T)=1.490 min (System B1, 10-90% MeCN over 3 min). ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.20-2.25 (m, 2H) 3.31-3.53 (m, 4H) 3.78 (s, 3H)5.27 (br s, 1H) 6.90-6.97 (m, 2H) 7.00 (d, J=8.53 Hz, 2H) 7.43-7.48 (m,2H) 7.57 (d, J=8.53 Hz, 2H) 7.93-7.96 (m, 1H) 8.19-8.22 (m, 1H) 9.63 (brs, 2H). MS (ESI+) for C₂₁H₂₂N₂O₄S m/z 409.2 (M+H)⁺. HPLC 100%,R_(T)=1.639 min (System A1, 10-97% MeCN over 3 min).

EXAMPLE 34

[0700]5-Chloro-N-[4-(pyrrolidin-3-yloxy)-1-naphthyl]thiophene-2-sulfonamideHydrochloride (General Method F)

[0701] The compound was prepared from intermediate 5 (0.20 g, 0.39mmol), Yield: 0.14 g (80%) of the title compound as a pale white solid.HPLC 99%, R_(T)=1.651 min (System B11, 10-90% MeCN over 3 min). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.23-2.26 (m, 2H) 3.28-3.39 (m, 2H) 3.40-3.56(m, 2H) 5.32 (br s, 1H) 6.99 (d, J=8.53 Hz, 1H) 7.13 (d, J=8.03 Hz, 1H)7.15 (d, J=4.02 Hz, 1H) 7.26 (d, J=4.02 Hz, 1H) 7.48-7.52 (m, 2H) 7.92(dd, J=6.53, 3.01 Hz, 1H) 8.25 (dd, J=6.53, 3.01 Hz, 1H) 9.60 (s, 1H).MS (ESI+) for C₁₈H₁₇ClN₂O₃S₂ m/z 409.2 (M+H)⁺. HPLC 99%, R_(T)=1.818 min(System A1, 10-97% MeCN over 3 min).

EXAMPLE 35

[0702] 4-Chloro-N-[4-(piperidin-3-yloxy)-1-naphthyl]benzenesulfonamideHydrochloride (General Method F)

[0703] The compound was prepared from intermediate 8 (0.26 g, 0.50mmol), Yield: 0.12 g (53%) of the title compound as a white solid. HPLC100%, R_(T)=1.872 min (System A1, 10-97% MeCN over 3 min). ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.95-1.99 (m, 2H) 2.14-2.19 (m, 2H) 3.11 (br s, 2H)3.26 (br s, 2H) 4.84 (br s, 1H) 6.92-6.99 (m, 2H) 7.44-7.51 (m, 2H)7.57-7.65 (m, 4H) 7.91 (d, J=7.53 Hz, 1H) 8.17 (d, J=7.03 Hz, 1H) 8.94(br s, 1H) 9.05 (br s, 1H) 10.11 (s, 1H). MS (ESI+) for C₂₁H₂₁ClN₂O₃Sm/z 415.2 (M+H)⁺. HPLC 99%, R_(T)=0.657 min (System B1, 10-90% MeCN over3 min).

EXAMPLE 36

[0704] 4-Methoxy-N-[4-(piperidin-3-yloxy)-1-naphthyl]benzenesulfonamideHydrochloride (General Method F)

[0705] The compound was prepared from intermediate 9 (0.19 g, 0.37mmol), Yield: 0.15 g (90%) of the title compound as a white solid. HPLC97%, R_(T)=1.508 min (System B1, 10-90% MeCN over 3 min). ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.96 (m, 2H) 2.16 (m, 2H) 3.10 (m, 2H) 3.26 (m,J=6.02 Hz, 2H) 3.78 (s, 3H) 4.82 (m, 1H) 6.95 (q, J=8.20 Hz, 1H) 7.01(d, J=9.04 Hz, 2H) 7.47 (m, 2H) 7.57 (m, 2H) 7.96 (m, 1H) 8.16 (m, 1H)8.96 (s, 1H) 9.07 (s, 1H) 9.81 (s, 1H). MS (ESI+) for C₂₂H₂₄N₂O₄S m/z413.4 (M+H)⁺. HPLC 97%, R_(T)=1.713 min (System A1, 10-97% MeCN over 3min).

EXAMPLE 37

[0706]5-Fluoro-2-methyl-N-[4-(piperidin-4-yloxy)-1-naphthyl]benzenesulfonamideHydrochloride (General Method F)

[0707] The compound was prepared from intermediate 10 (0.24 g, 0.47mmol). Yield: 0.21 g (99%) of the title compound as an off-white solid.HPLC 100%, R_(T)=1.823 min (System A1, 10-97% MeCN over 3 min). ¹H NMR(400 MHz, CH₃OH-d4) δ ppm 2.13 (m, 4H) 2.42 (s, 3H) 3.18 (m, 2H) 3.37(m, 2H) 4.83 (m, 1H) 6.81 (d, J=8.53 Hz, 1H) 6.97 (d, J=8.03 Hz, 1H)7.10 (m, 1H) 7.24 (m, J=8.53, 5.52 Hz, 1H) 7.35 (m, 3H) 7.83 (m, 1H). MS(ESI+) for C₂₂H₂₃FN₂O₃S m/z 415.2 (M+H)⁺. HPLC 96%, R_(T)=1.628 min(System B1, 10-90% MeCN over 3 min).

EXAMPLE 38

[0708]5-Chloro-N-[4-(piperidin-4-yloxy)-1-naphthyl]thiophene-2-sulfonamideHydrochloride (General Method F)

[0709] The compound was prepared from tert-butyl 4-[(4-{[(5-fluoro-2methylphenyl)sulfonyl]amino}-1-naphthyl)oxy]piperidine-1-carboxylate(0.24 g, 0.46 mmol). Yield: 0.16 g (76%) of the title compound as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.96-2.03 (m, 2H) 2.16-2.22(m, 2H) 3.09-3.14 (m, 2H) 3.25-3.31 (m, 2H) 4.86-4.89 (m, 1H) 7.04-7.11(m, 2H) 7.16 (d, J=4.02 Hz, 1H) 7.26 (d, J=4.02 Hz, 1H) 7.48-7.53 (m,2H) 7.92-7.94 (m, 1H) 8.19-8.21 (m, 1H) 9.06 (br s, 1H) 10.36 (br s,1H). MS (ESI+) for C₁₉H₁₉ClN₂O₃S₂ m/z 423.0 (M+H)⁺. HPLC 99%,R_(T)=1.861 min (System A1, 10-97% MeCN over 3 min).

EXAMPLE 39

[0710]4-Chloro-N-{4-[(3S)-pyrrolidin-3-yloxy]-1-naphthyl}benzenesulfonamideHydrochloride (General Method F)

[0711] The compound was prepared from tert-butyl(3S)-3-[(4-{[(4-chlorophenyl)sulfonyl]amino}-1-naphthyl)oxy]pyrrolidine-1-carboxylate(0.22 g, 0.44 mmol). Yield: 0.15 g (78%) of the title compound as ayellow solid. ¹H NMR (400 MHz, CH₃OH-d₄) δ ppm 2.37-2.49 (m, 2H)3.52-3.56 (m, 2H) 3.61-3.71 (m, 2H) 5.37 (br s, 1H) 6.87 (d, J=8.03 Hz,1H) 7.14 (d, J=8.03 Hz, 1H) 7.38-7.47 (m, 4H) 7.61 (d, J=8.53 Hz, 2H)7.83 (d, J=8.03 Hz, 1H) 8.22 (d, J=8.03 Hz, 1H). MS (ESI+) forC₂₀H₁₉ClN₂O₃S m/z 403.2 (M+H)⁺. HPLC 100%, R_(T)=1.826 min (System A1,10-97% MeCN over 3 min).

EXAMPLE 40

[0712]4-Chloro-N-{4-[(3R)-pyrrolidin-3-yloxy]-1-naphthyl}benzenesulfonamideHydrochloride (General Method F)

[0713] The compound was prepared from tert-butyl(3R)-3-[(4-{[(4-chlorophenyl)sulfonyl]amino}-1-naphthyl)oxy]pyrrolidine-1-carboxylate(0.37 g, 0.74 mmol). Yield: 0.27 g (82%) of the title compound as aoff-white solid. ¹H NMR (400 MHz, CH₃OH-d₄) δ ppm 2.37-2.49 (m, 2H)3.52-3.56 (m, 2H) 3.61-3.71 (m, 2H) 5.37 (br s, 1H) 6.88 (d, J=8.53 Hz,1H) 7.15 (d, J=8.03 Hz, 1H) 7.39-7.47 (m, 4H) 7.60-7.62 (m, 2H) 7.83 (d,J=7.53 Hz, 1H) 8.22 (d, J=8.03 Hz, 1H). MS (ESI+) for C₂₀H₁₉ClN₂O₃S m/z403.2 (M+H)⁺. HPLC 100%, R_(T)=1.815 min (System A1, 10-97% MeCN over 3min). TABLE 4

EXAM- PLE R² R³ R⁴ 41 N-(4-Methylphenyl)-4-(4-methylpiperazin-1-yl)thieno[3,2-c]pyridine-2-sulfonamide hydrochloride

H

42 2-Bromo-4-(4-methyl-piperazin-1-yl)- thieno[3,2-c]pyridine-3-sulfonicacid p- tolylamide hydrochloride Br

43 4-(4-Methylpiperazin-1-yl)-N- phenylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride

H

44 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2- sulfonic acid(3-fluoro-5-trifluoromethyl- phenyl)-amide hydrochloride

H

45 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2- sulfonic acid(4-chloro-phenyl)-amide hydrochloride

H

46 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2- sulfonic acid(4-isopropyl-phenyl)-amide hydrochloride

H

47 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2- sulfonic acid p-tolylamidehydrochloride

H

48 4-(4-Methylpiperazin-1-yl)-N-(2- cyclohex-1-en-1-ylethyl) thieno[3,2-c]pyridine-2-sulfonamide hydrochloride

H

49 2-(4-(4-Methylpiperazin-1-yl) thieno [3,2- c]pyridin-2-ylsulfonyl)-1,2,3,4- tetrahydroisoquinoline hydrochloride

H

50 4-(4-Methylpiperazin-1-yl)-N-(2-thien-2- ylethyl) thieno [3,2-c]pyridine-2- sulfonamide hydrochloride

H

51 4-(4-Methylpiperazin-1-yl)-N-[1-(1- naphthyl) ethyl] thieno [3,2-c]pyridine-2- sulfonamide hydrochloride

H

52 4-(4-Methylpiperazin-1-yl)-N-(4- hexylphenyl) thieno [3,2-c]pyridine-2- sulfonamide hydrochloride

H

53 N-(3-Chlorobenzyl)-4-(4-methylpiperazin- 1-yl) thieno [3,2-c]pyridine-2-sulfonamide

H

54 4-(4-Methylpiperazin-1-yl)-N-[1-(4- fluorophenyl) ethyl] thieno[3,2-c]pyridine-2-sulfonamide hydrochloride

H

55 N-(2,3-Difluorobenzyl)-4-(4- methylpiperazin-1-yl) thieno[3,2-c]pyridine-2-sulfonamide hydrochloride

H

56 4-(4-Methylpiperazin-1-yl)-N-(4-chloro-2, 5-dimethoxyphenyl) thieno[3,2-c]pyridine-2-sulfonamide hydrochloride

H

57 2-Bromo-4-(4-methylpiperazin-1-yl)-N- (2-cyclohex-1-en-1-ylethyl)thieno [3,2-c]pyridine-3-sulfonamide hydrochloride Br

58 2-[2-Bromo-4-(4-methyl-piperazin-1-yl)-benzo[b]thiophene-3-sulfonyl]- 1,2,3,4-tetrahydro-isoquinoline Br

59 2-Bromo-4-(4-methylpiperazin-1-yl)-N- [1-(4-fluorophenyl) ethyl]thieno [3,2-c]pyridine-3-sulfonamide hydrochloride Br

60 2-Bromo-4-(4-methylpiperazin-1-yl)-N-(4-chloro)-(2,5-dimethoxyphenyl) thieno [3,2- c] pyridine-3-sulfonamidehydrochloride Br

61 N-(3,4-Dichlorophenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride

H

62 N-(2,4-Difluorophenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride

H

63 4-Piperazin-1-yl-N-[-3- (trifluoromethyl)phenyl]thieno[3,2-c]pyridine-2-sulfonamide hydrochloride

H

64 N-(3-Ethylphenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride

H

65 N-(3,4-Dimethoxyphenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride

H

66 N-(4-Bromo-2-methylphenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride

H

67 2-(4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonyl)-1,2,3,4-tetrahydro-isoquinoline hydrochloride

H

68 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2- sulfonic acid(2-thiophen-2-yl-ethyl)- amide hydrochloride

H

69 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2- sulfonic acid(4-chloro-2,5-dimethoxy- phenyl)-amide hydrochloride

H

70 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2- sulfonic acidphenethyl-amide hydrochloride

H

71 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2- sulfonic acid(2,6-diethyl-phenyl)-amide hydrochloride

H

72 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2- sulfonic acid(3-phenyl-propyl)-amide hydrochloride

H

73 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2- sulfonic acid(3,3-diphenyl-propyl)-amide hydrochloride

H

74 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2- sulfonic acid[2-(5-methoxy-1H-indol-3- yl)-ethyl]-amide hydrochloride

H

75 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2- sulfonic acid4-trifluoromethyl- benzylamide hydrochloride

H

76 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2- sulfonic acidbenzyl-ethyl-amide hydrochloride

H

77 N-(3-Ethylphenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-3-sulfonamide hydrochloride H

78 N-(4-Isopropylphenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-3-sulfonamide hydrochloride H

79 N-(4-Methylphenyl)-4-(pyrrolidin-3-yloxy)thieno[3,2-c]pyridine-2-sulfonamide hydrochloride

H

80 N-(4-Methylphenyl)-4-(piperidin-4-yloxy)thieno[3,2-c]pyridine-2-sulfonamide hydrochloride

H

81 N-(2,3-Difluorobenzyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride

H

82 N-(3-Chlorobenzyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride

H

[0714]

[0715] Intermediate 47

[0716] (2E)-3-(5-Bromothien-2-yl) Acrylic Acid

[0717] Malonic acid (44.40 g, 426.7 mmol) was added to a mixture of5-bromothiophene-2-carbaldehyde (50 g, 261.7 mmol), piperidine (2.84 mL)and pyridine (150 mL). The mixture was refluxed for 1 h at 80° C. andthan at 100° C. over night. The volatiles were evaporated and theresidue was dissolved in water and acidified with hydrochloric acid (pH2). The crude product was crystallized in ethanol. Yield: 55.24 g(90.5%). ¹H NMR (270 MHz, CH₃OH-d₄) δ ppm 6.14 (d, J=15.83 Hz, 1H)7.11-7.16 (m, 2H) 7.68 (d, J=16.36 Hz, 1H); MS 233.1 (M−H)⁺; Purity(HPLC) 94%.

[0718] Intermediate 48

[0719] (2E)-3-(5-Bromothien-2-yl) Acryloyl Azide

[0720] Thionyl chloride (1.04 mL) was added to a solution of(2E)-3-(5-bromothien-2-yl) acrylic acid (1.04 g, 4.46 mmol) inchloroform (20 mL) and the mixture was refluxed for 2 h at 75° C. andthan used in the next step. The above solution was added drop wise to astirred suspension of sodium azide (0.58 g, 8.93 mmol), dioxane (3 mL)and water (3 mL) in an ice bath. After 10 min a precipitate appearedwhich was filtered off and washed with water. The residue was dissolvedin dichloromethane, dried with MgSO₄, filtered and the solvent wasremoved to afford: 0.96 g (83.4%). ¹H NMR (270 MHz CH₃OH-d₄) δ ppm 6.20(d, J=15.57 Hz, 1H) 7.15-7.25 (m, 2H) 7.80 (d, J=15.57 Hz, 1H); MS 258.1(M−H)⁺; Purity (HPLC) 65%.

[0721] Intermediate 49

[0722] 2-Bromothieno[3,2-c]pyridin-4 (5H)-one

[0723] A solution of (2E)-3-(5-bromothien-2-yl) acryloyl azide (18.00 g,69.7 mmol) solved in dichloromethane (100 mL) was added dropwise todiphenyl ether (90 mL) at 150° C. The temperature was increased to 220°C. for 1 h. The mixture was cooled to room temperature followed by theaddition of ether. The solid precipitated and was separated byfiltration. Yield: 13.58 g (84.6%). ¹H NMR (270 MHz, DMSO-d₆) δ ppm 6.82(d, J=7.13 Hz, 1H) 7.27 (d, J=6.86 Hz, 1H) 7.54 (s, 1H) 11.55 (s, 1H);MS 230.1 (M−H)⁺; Purity (HPLC) 92%.

[0724] Intermediate 50

[0725] 2-Bromo-4-chloro-thieno[3,2-c]pyridine

[0726] Phosphorus oxychloride (4.08 g, 26.6 mmol) was added dropwise to2-bromothieno[3,2-c]pyridin-4 (5H)-one (2.04 g, 8.87 mmol) at 0° C. Themixture was heated at 135° C. for 2.5 h, then carefully poured over icewater. The precipitated was collected by filtration and dried to yield1.78 g (80.7%) of title product. ¹H NMR (270 MHz, CH₃OH-d₄) δ ppm 7.67(d, 1H) 7.88 (dddd, J=6.33 Hz, 2H) 8.19 (d, J=5.54 Hz, 1H); MS 248.0(M−H)⁺; Purity (HPLC) 100

[0727] Intermediate 51 and Intermediate 52

[0728] 4-Chlorothieno[3,2-c]pyridine-2-sulfonyl Chloride and2-bromo-4-chlorothieno[3,2-c]pyridine-3-sulfonyl Chloride

[0729] n-Butyl lithium (1.5 mL, 2.4 mmol) was added to2-bromo-4-chlorothieno[3,2-c]pyridine (0.5 g, 2 mmol) dissolved in dryTHF (15 ml) at −78° C. under nitrogen. The mixture was stirred for 40min. The above solution was added to a dry ether saturated with SO₂(gas) at −78° C. The mixture was warmed to room temperature, followed bythe addition of ether. The precipitate was separated by filtration. Thetwo title products were obtained and taken to the next step withoutfurther purification as follows: N-chlorosuccinimide (2.07 g, 10.3 mmol)was added to [(4-chlorothieno[3,2-c]pyridin-2-yl)sulfonyl]lithium and[(2-bromo-4-chlorothieno[3,2-c]pyridin-3-yl)sulfonyl]lithium indichloromethane (150 mL) at 0° C. The mixture was heated at 60° C. for 2h, extracted with water (3×50 mL). The organic phase was separated,dried with MgSO₄, filtrated and the volatiles were eliminated by vacuumdistillation. The crude products were used in the next step withoutfurther purification.

[0730] Intermediate 53 and Intermediate 54

[0731] 4-Chloro-2-thieno[3,2-c]pyridine-2-sulfonic Acid p-tolylamide and2-bromo-4-chlorothieno[3,2-c]pyridine-3-sulfonic Acid p-tolylamide

[0732] p-Toludine (30 mg, 2.87 mmol) was added to a solution of4-chlorothieno[3,2-c]pyridine-2-sulfonyl chloride and2-bromo-4-chlorothieno[3,2-c]pyridine-3-sulfonyl chloride (0.07 g, 0.26mmol) in dichloromethane and pyridine (0.19 mL). The reaction wasstirred at room temperature for 2 h. The solvent was removed and thecrude mixture was taken to the next step without further purification.

EXAMPLE 41 and EXAMPLE 42

[0733] 4-(4-Methyl-piperazin-1-yl)-thieno[3,2-c]pyridine-2-sulfonic Acidp-tolylamide Hydrochloride and2-bromo-4-(4-methyl-piperazin-1-yl)-thieno[3,2-c]pyridine-3-sulfonicAcid p-tolylamide Hydrochloride

[0734] A mixture of 4-chloro-2-thieno[3,2-c]pyridine-2-sulfonic acidp-tolylamide and 2-bromo-4-chloro-thieno[3,2-c]pyridine-3-sulfonic acidp-tolylamide (70 mg, 0.21 mmol) in DMSO (2 mL), 1-methyl piperazine(0.344 mL, 3.1 mmol) and K₂CO₃ (28.5 mg, 0.21 mmol) was heated to 100°C. over night. The reaction mixture was dissolved in water and extractedwith ethyl acetate (3×10 mL). The organic layers were collected and thesolvent was removed. The products were purified by HPLC to afford 1.9 mgof 4-(4-Methyl-piperazin-1-yl)-thieno[3,2-c]pyridine-2-sulfonic acidp-tolylamide. The free base was converted into the hydrochloride salt bytreatment with HCl in ether: ¹H NMR (270 MHz, Methanol-d₄) δ ppm 2.26(s, 3H) 2.98 (s, 3H) 3.40-3.55 (m, 8H) 7.02-7.10 (m, 6H) 7.55 (d, J=5.81Hz, 1H) 7.69 (s, 1H) 8.13 (d, J=5.81 Hz, 1H); LC-MS 403 (M+H)⁺; Purity(LC-MS) 92% and 3.8 mg2-bromo-4-(4-methyl-piperazin-1-yl)-thieno[3,2-c]pyridine-3-sulfonicacid p-tolylamide. The free base was converted into the hydrochloridesalt by treatment with HCl in ether: ¹H NMR (270 MHz, Methanol-d₄) δ ppm2.21 (s, 1H) 3.00 (d, 3H) 3.50-3.77 (m, 8H) 7.00-7.10 (m, 6H) 7.63 (d,J=5.81 Hz, 1H) 8.19 (d, J=5.81 Hz, 1H); LC-MS 481 (M+H)⁺; Purity (LC-MS)98%.

[0735] Reaction of Sulfonyl Chloride with Amines (Method H)

[0736] To a solution of the amine (1.3 equiv.) and pyridine (8 equiv.)in DCM was added the sulfonyl chloride (1 equiv.) and the reactionmixture was stirred over night. After addition of Trisamine™ (ca 2equiv.), the mixture was gently shaken for additional 3 h. Thesuspension was then filtered through a short silica plug by the aid ofDCM and ethyl acetate. The solvent was evaporated, and the residue wasdissolved in DCM and washed with 1 M aqueous HCl (2 times). The combinedorganic phases were dried (MgSO₄), filtered, and the solvent was removedto give the sulfonamide product. In cases of low-purity material, theproducts were purified by silica gel flash chromatography. The productsare used in the next step (Procedure B).

[0737] Coupling with Aromatic Amines (Method I)

[0738] To the reaction mixtures from the Method H, dissolved in DMSO (2mL), amines (15 equiv.) and K₂CO₃ (1 equiv.) are added. The reactionsare stirred at 100° C. for 24 and than concentrated. The products arepurified by LC-MS. The solvents are removed under vacuum by SpeedVac andpurified by preparative LC/MS. The products that were not pure enough(Purity ≦90%) were purified by preparative chromatography usingacetonitrile-water gradients containing 0.1% triflouroacetic acid. AfterHPLC analysis fractions that were ≧90% pure were collected andconcentrated. Deprotection of the amine in the piperazine was performedby first dissolving the substance in methanol and adding portions of 1MHCl/ether. The reactions are analyzed by TLC. The solvents wereconcentrated under vacuum by a SpeedVac.

[0739] Deprotection of BOC-Group (Method L)

[0740] The sulfone or sulfonamide derivative (prepared by Methods H andI) were dissolved in a small amount of MeOH/DCM 1:1 and treated with anexcess of 1 M HCl in diethyl ether. Stirring at ambient temperatureovernight resulted in a precipitate which were collected by filtrationto give the products as their corresponding hydrochloride salts.

EXAMPLE 43

[0741]4-(4-Methylpiperazin-1-yl)-N-phenylthieno[3,2-c]pyridine-2-sulfonamideHydrochloride

[0742] The synthesis was preformed essentially as described in MethodH-L. Yield: 8.1 mg (33.8%).

[0743]¹H NMR (270 MHz, CH₃OH-d₄) δ ppm 8.13 (d, J=5.81 Hz, 1H) 7.67 (s,1H) 7.54 (d, J=5.81 Hz, 1H) 7.55-7.53 (m, 5H) 2.97 (s, 3H) (4H obscuredby solvent signal); LC-MS 389 (M−H)⁺; Purity (HPLC) 100%.

EXAMPLE 44

[0744] 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic Acid(3-fluoro-5-trifluoromethylphenyl)-amide Hydrochloride

[0745]4-[2-(3-Fluoro-5-trifluoromethyl-phenylsulfamoyl)-thieno[3,2-c]pyridin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (0.235 mmol, 1 equiv.) was used as thethienopyridine in Method H-L. Yield: 25.7 mg HPLC: t_(R)=3.395 (System:5% to 50% ACN in 3 min, C8), Purity: 100%, LC/MS: t_(R)=1.375 (System:30% to 60% ACN in 1.5 min, Hypersil BDS), Purity: 99%. MS: 461 (M+1) ¹HNMR (270 MHz, CH₃OH-d₄) δ ppm 3.47 (m, 4H) 3.53 (s, 1H) 3.87 (m, 4H)7.21 (m, 1H) 7.29 (m, 1H) 7.33 (s, 1H) 7.66 (d, J=6.33 Hz, 1H).

EXAMPLE 45

[0746] 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic Acid(4-chloro-phenyl)-amide Hydrochloride

[0747] 4-Chloro-thieno[3,2-c]pyridine-2-sulfonic acid(3-fluoro-5-trifluoromethyl-phenyl)-amide (0.208 mmol, 1 equiv.) wasused as the thienopyridine in Method H-L. Yield: 7.2 mg HPLC:t_(R)=3.039 (System: 5% to 50% ACN in 3 min, C8), Purity: 100%, LC/MS:t_(R)=0.905 (System: 30% to 60% ACN in 1.5 min, Hypersil BDS), Purity:97%. MS: 409 (M+1). ¹H NMR (270 MHz, CH₃OH-d₄) δ ppm 3.50 (m, 4H) 3.91(m, 4H) 7.25 (m, 4H) 7.71 (dd, J=6.33, 0.53 Hz, 1H) 7.96 (d, J=0.79 Hz,1H) 8.04 (d, J=6.33 Hz, 1H).

EXAMPLE 46

[0748] 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic Acid(4-isopropyl-phenyl)-amide Hydrochloride

[0749] 4-Chloro-thieno[3,2-c]pyridine-2-sulfonic acid(4-isopropyl-phenyl)-amide (0.201 mmol, 1 equiv.) was used as thethienopyridine in Method H-L. Yield: 6.9 mg HPLC: t_(R)=3.255 (System:5% to 50% ACN in 3 min, C8), Purity: 95%, LC/MS: t_(R)=1.255 (System:30% to 60% ACN in 1.5 min, Hypersil BDS), Purity: 98%. MS: 417 (M+1). ¹HNMR (270 MHz, CH₃OH-d₄) δ ppm 1.18 (d, J=6.86 Hz, 6H) 2.83 (m, 2H) 3.52(m, 4H) 4.00 (m, 4H) 7.14 (m, 3H) 7.75 (d, J=6.60 Hz, 1H) 8.02 (m, 1H).

EXAMPLE 47

[0750] 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic Acidp-tolylamide Hydrochloride

[0751] To a solution of 4-chloro-thieno[3,2-c]pyridine-2-sulfonylchloride (0.640 g, 2.39 mmol) in DCM (20 mL) was added pyridine (1.9 mL,23.9 mmol) followed byp-tolylamine (0.307 g, 2.86 mmol). The reactionmixture was stirred at room temperature for 16 hours. The mixture wasconcentrated and re-dissolved in DMSO (10 mL), piperazine-1-carboxylicacid tert-butyl ester (1.34 g, 7.17 mmol) and K₂CO₃ (0.989 g, 7.17 mmol)were added. The mixture was stirred at 100° C. for 16 hours and thenconcentrated. The crude reaction mixture was dissolved in EtOAc (100 mL)and washed with brine (2×50 mL). The organic phase was dried (Na₂SO₄)and concentrated. The crude intermediate was purified by columnchromatography on silica using EtOAc/n-pentane (1:1) as eluent. Theintermediate was dissolved in EtOAc/MeOH and diethyl ether saturatedwith HCl (g) was added. The mixture was stirred at room temperature for16 hours. The precipitate was collected by filtration and washed withdiethyl ether/n-pentane to give 0.475 g of the crude product.Purification by preparative reversed phase HPLC gave 0.133 g of the pureproduct: ¹H NMR (DMSO-d₆, 25° C., 270.17 MHz) δ 10.61 (br s, 1H), 9.23(br s, 2H), 8.13 (d, J=5.80 Hz, 1H), 7.91 (s, 1H); 7.67 (d, J=5.80 Hz,1H), 7.09-7.07 (m, 4H), 3.68-3.59 (m, 4H), 3.33-3.22 (m, 4H), 2.20 (s,3H); m/z (posESI) 399 (M+H).

EXAMPLE 48

[0752]4-(4-Methylpiperazin-1-yl)-N-(2-cyclohex-1-en-1-ylethyl)thieno[3,2-c]pyridine-2-sulfonamideHydrochloride

[0753] The synthesis was preformed essentially as described in MethodH-L. Yield: 25.6 mg ¹H NMR (270 MHz, DMSO-d₆) δ ppm 10.49-10.48 (m, 1H)8.23-7.95 (m, 3H) 7.72-7.71 (m, 1H) 5.34-5.33 (m, 1H) 4.14-4.11 (m, 2H)3.53-3.51 (m, 2H) 3.29-3.25 (m, 2H) 2.98-2.97 (m, 2H) 2.85 (s, 3H)2.04-1.81 (m, 4H) 1.57-1.15 (m, 8H); LC-MS 420.17 (M−H)⁺; Purity (LC-MS)97%.

EXAMPLE 49

[0754]2-(4-(4-Methylpiperazin-1-yl)thieno[3,2-c]pyridin-2-ylsulfonyl)-1,2,3,4-tetrahydroisoquinolineHydrochloride

[0755] The synthesis was preformed essentially as described in MethodH-L. Yield: 15.5 mg ¹H NMR (270 MHz, DMSO-d₆) δ ppm 10.49-10.48 (m, 1H)8.17-8.15 (m, 1H) 7.86-7.85 (m, 1H) 7.70-7.65 (m, 2H) 7.28-7.12 (m, 3H)3.97-3.94 (m, 2H) 3.87-3.85 (m, 2H) 3.25-3.18 (m, 2H) 2.84 (s, 3H)1.67-1.65 (m, 2H) 3.51-3.34 (6H obscured by solvent signal); LC-MS428.13 (M−H)⁺; Purity (LC-MS) 99%.

EXAMPLE 50

[0756]4-(4-Methylpiperazin-1-yl)-N-(2-thien-2-ylethyl)thieno[3,2-c]pyridine-2-sulfonamideHydrochloride

[0757] The synthesis was preformed essentially as described in MethodH-L. Yield: 29.5 mg ¹H NMR (270 MHz, DMSO-d₆) δ ppm 10.28-10.27 (m, 1H)8.34-8.33 (m, 1H) 8.19-8.17 (m, 1H) 8.01-8.00 (m, 1H) 7.71-7.69 (m, 1H)7.31-7.30 (m, 1H) 6.91-6.87 (m, 1H) 4.13-4.10 (m, 2H) 3.53-3.51 (m, 2H)3.29-3.25 (m, 2H) 3.17-3.16 (m, 2H) 2.99-2.95 (m 4H) 2.86 (s, 3H); LC-MS422.09 (M−H)⁺; Purity (LC-MS) 99%.

EXAMPLE 51

[0758]4-(4-Methylpiperazin-1-yl)-N-[1-(1-naphthyl)ethyl]thieno[3,2-c]pyridine-2-sulfonamideHydrochloride

[0759] The synthesis was preformed essentially as described in MethodH-L. 20.1 mg ¹H NMR (270 MHz, DMSO-d₆) δ ppm 10.28-10.27 (m, 1H)8.85-8.84 (m, 1H) 8.02-8.01 (m, 1H) 7.67-7.60 (m, 4H) 7.53-7.50 (m, 2H)7.39-7.36 (m, 2H) 4.72-4.70 (m, 1H) 3.87-3.84 (m, 1H) 3.72-3.70 (m, 1H)3.23-3.13 (m, 4H) 2.84 (s, 3H) 1.42-1.40 (m 3H); LC-MS 466.15 (M−H)⁺;Purity (LC-MS) 99%.

EXAMPLE 52

[0760]4-(4-Methylpiperazin-1-yl)-N-(4-hexylphenyl)thieno[3,2-c]pyridine-2-sulfonamideHydrochloride

[0761] The synthesis was preformed essentially as described in MethodH-L. 8.0 mg ¹H NMR (270 MHz, DMSO-d₆) δ ppm 10.39-10.38 (m, 1H)8.16-8.15 (m, 1H) 7.90-7.89 (m, 1H) 7.66-7.65 (m, 1H) 7.09-7.08 (m, 4H)4.00-3.98 (m, 2H) 3.51-3.48 (m, 2H) 3.26-3.22 (m, 2H) 2.85 (s, 3H)2.49-2.45 (m, 2H) 1.48-1.46 (m, 2H) 1.24-1.22 (m, 8H) 0.82-0.81 (m, 3H);LC-MS 472.20 (M−H)⁺; Purity (LC-MS) 98%.

EXAMPLE 53

[0762]N-(3-Chlorobenzyl)-4-(4-methylpiperazin-1-yl)thieno[3,2-c]pyridine-2-sulfonamideHydrochloride

[0763] The synthesis was preformed essentially as described in MethodH-L. 30.7 mg ¹H NMR (270 MHz, DMSO-d₆) δ ppm 10.25-10.24 (m, 1H)8.78-8.77 (m, 1H) 8.18-8.17 (m, 1H) 7.91-7.90 (m, 1H) 7.68-7.67 (m, 1H)7.26-7.19 (m, 3H) 4.21-4.20 (m, 2H) 4.08-4.05 (m, 2H) 3.54-3.51 (m, 2H)3.28-3-23 (m, 2H) 2.87 (s, 3H) 2.84-2.60 (2H obscured by solventsignal); LC-MS 436.08 (M−H)⁺; Purity (LC-MS) 94%

EXAMPLE 54

[0764]4-(4-Methylpiperazin-1-yl)-N-[1-(4-fluorophenyl)ethyl]thieno[3,2-c]pyridine-2-sulfonamideHydrochloride

[0765] The synthesis was preformed essentially as described in MethodH-L. 32.9 mg ¹H NMR (270 MHz, DMSO-d₆) δ ppm 10.16-10.15 (m, 1H)8.75-8.73 (m, 1H) 7.63-7.62 (m, 2H) 7.25-7.24 (m, 2H) 6.91-6.88 (m, 2H)4.58-4.55 (m, 1H) 4.02-3.95 (m, 2H) 3.55-3.53 (m, 2H) 3.25-3-21 (m, 2H)2.68 (s, 3H) 1.31-1.30 (m, 3H) 2.70-2.64 (2H obscured by solventsignal); LC-MS 434.12 (M−H)⁺; Purity (LC-MS) 92%.

EXAMPLE 55

[0766]N-(2,3-Difluorobenzyl)-4-(4-methylpiperazin-1-yl)thieno[3,2-c]pyridine-2-sulfonamideHydrochloride

[0767] The synthesis was preformed essentially as described in MethodH-L. 26.7 mg ¹H NMR (270 MHz, DMSO-d₆) δ ppm 10.36-10.35 (m, 1H)8.82-8.81 (m, 1H) 7.96-7.95 (m, 1H) 7.69-7.68 (m, 1H) 7.27-7.10 (m, 2H)4.26-4.25 (m, 2H) 4.11-4.08 (m, 2H) 3.54-3.52 (m, 2H) 3.28-3-24 (m, 2H)2.68 (s, 3H) 2.86-2.60 (2H obscured by solvent signal); LC-MS 438.10(M−H)⁺; Purity (LC-MS) 93%.

EXAMPLE 56

[0768]4-(4-Methylpiperazin-1-yl)-N-(4-chloro-2,5-dimethoxyphenyl)thieno[3,2-c]pyridine-2-sulfonamideHydrochloride

[0769] The synthesis was preformed essentially as described in MethodH-L. 14.6 mg ¹H NMR (270 MHz, DMSO-d₆) δ ppm 10.27-10.26 (m, 1H)10.14-10.13 (m, 1H) 8.18-8.17 (m, 1H) 7.83-7.82 (m, 1H) 7.69-7.68 (m,1H) 7.09-7.07 (m, 2H) 4.00 (s 2H) 3.76-3.75 (m, 2H) 3.51-3.48 (m, 2H)3.24-3.22 (m, 2H) 2.85 (s, 3H); LC-MS 482.08 (M−H)⁺; Purity (LC-MS) 95%.

EXAMPLE 57

[0770]2-Bromo-4-(4-methylpiperazin-1-yl)-N-(2-cyclohex-1-en-1-ylethyl)thieno[3,2-c]pyridine-3-sulfonamideHydrochloride

[0771] The synthesis was preformed essentially as described in MethodH-L. 4.6 mg ¹H NMR (270 MHz, DMSO-d₆) δ ppm 10.30-10.29 (m, 1H)8.31-8.27 (m, 2H) 7.89-7.88 (m, 1H) 5.27-5.26 (m, 1H) 3.68-3.52 (m, 4H)3.05-3.04 (m, 2H) 2.88-2.87 (m, 3H) 2.04-2.03 (m, 2H) 2.77-1.81 (m, 2H)1.54-1.15 (m, 101H); LC-MS 498.08 (M−H)⁺; Purity (LC-MS) 93%.

EXAMPLE 58

[0772]2-[2-Bromo-4-(4-methyl-piperazin-1-yl)-benzo[b]thiophene-3-sulfonyl]-1,2,3,4-tetrahydro-isoquinolineHydrochloride

[0773] The synthesis was preformed essentially as described in MethodH-L. Yield: 3.7 mg ¹H NMR (270 MHz, DMSO-d₆) δ ppm 10.30-10.29 (m, 1H)9.24-9.22 (m, 1H) 8.09-8.08 (m, 1H) 7.67-7.35 (m, 7H) 4.69-4.66 (m, 1H)2.86-2.85 (m, 3H) 1.50-1.48 (m, 3H) 3.23-2.51 (8H obscured by solventsignal); LC-MS 544.06 (M−H)⁺; Purity (LC-MS) 92%.

EXAMPLE 59

[0774]2-Bromo-4-(4-methylpiperazin-1-yl)-N-[1-(4-fluorophenyl)eth-2-yl]thieno[3,2-c]pyridine-3-sulfonamideHydrochloride

[0775] The synthesis was preformed essentially as described in MethodH-L. Yield: 4.3 mg ¹H NMR (270 MHz, DMSO-d₆) δ ppm 10.35-10.34 (m, 1H)9.16-9.14 (m, 1H) 8.23-8.22 (m, 1H) 7.80-7.79 (m, 1H) 7.26-7.25 (m, 1H)4.55-4.52 (m, 1H) 3.54-3.52 (m, 2H) 2.88-2.87 (m, 3H) 1.38-1.36 (m, 3H)3.17-2.83 (6H obscured by solvent signal); LC-MS 512.04 (M−H)⁺; Purity(LC-MS) 93

EXAMPLE 60

[0776]2-Bromo-4-(4-methylpiperazin-1-yl)-N-(4-chloro)-(2,5-dimethoxyphenyl)thieno[3,2-c]pyridine-3-sulfonamideHydrochloride

[0777] The synthesis was preformed essentially as described in MethodH-L. Yield: 0.7 mg, LC-MS 561.91(M−H)⁺; Purity (LC-MS) 95%.

EXAMPLE 61

[0778]N-(3,4-dichlorophenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamideHydrochloride

[0779] 3,4-Dichloroaniline (0.49 mmol), was dissolved in acetonitrile (1mL) and pyridine (0.440 mL, 4.03 mmol) was added to a solution of4-chlorothieno[3,2-c]pyridine-2-sulfonyl chloride (0.445 mmol) dissolvedin acetonitrile (1 mL). The reaction was shaken for 1 h, controlled withHPLC and the solvent was removed. The crude product was used in the nextstep without further purification. To the reaction mixture from theprevious step, dissolved in DMSO (1 mL), piperazine (15 equiv.) andK₂CO₃ (1 equiv.) was added. The reaction was stirred at 100° C. for 24and than concentrated. The product was purified by LC-MS and gave 5.8 mg(2.6%) of the title product. ¹H NMR (270 MHz, CH₃OH-d₄) δ ppm 8.07-8.05(m, 2H) 7.73 (d, J=6.60 Hz, 1H) 7.46-7.41 (m, 2H) 7.16 (dd, J=8.71, 2.38Hz, 1H) 3.94-3.90 (m, 4H) 3.92 (m, 4H) 3.53-3.50 (m, 4H); LC-MS 443(M−H)⁺; Purity (HPLC) 95%.

EXAMPLE 62

[0780]N-(2,4-Difluorophenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamideHydrochloride

[0781] The synthesis was preformed essentially as described in MethodH-L. Yield: 4.3 mg (2.1%).

[0782]¹H NMR (270 MHz, CH₃OH-d₄) δ ppm 8.22 (s, 1H) 8.07-8.01 (m, 2H)7.79-7.72 (m, 1H) 7.55-7.47 (m, 1H) 7.04-6.94 (m, 2H) 4.00-3.96 8 m, 4H)3.53-3.43 (m, 4H) 2.66 (s, 1H); LC-MS 411 (M−H)⁺; Purity (HPLC) 98%.

EXAMPLE 63

[0783]4-Piperazin-1-yl-N-[-3-(trifluoromethyl)phenyl]thieno[3,2-c]pyridine-2-sulfonamideHydrochloride

[0784] The synthesis was preformed essentially as described in MethodH-L. Yield: 2.6 mg (1.2%).

[0785]¹H NMR (270 MHz, CH₃OH-d₄) δ ppm 8.05 (d, J=6.60 Hz, 2H) 7.81-7.60(m, 3H) 7.50-7.47 (m, 2H) 3.94-3.90 (m, 4H) 3.56-3.49 (m, 4H); LC-MS 443(M−H)⁺; Purity (HPLC) 99%.

EXAMPLE 64

[0786]N-(3-Ethylphenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamideHydrochloride

[0787] The synthesis was preformed essentially as described in MethodH-L. Yield: 1.4 mg (0.7%).

[0788]¹H NMR (270 MHz, CH₃OH-d₄) δ ppm 8.35 (s, 1H) 7.58-6.92 (m, 7H)3.54-3.44 (m, 2H) 3.01-2.95 (m, 4H) 2.66 (s, 1H) 2.18-2.01 (m, 3H));LC-MS 403 (M−H)⁺; Purity (HPLC) 100

EXAMPLE 65

[0789]N-(3,4-Dimethoxyphenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamideHydrochloride

[0790] The synthesis was preformed essentially as described in MethodH-L. Yield: 7.7 mg (3.6%).

[0791]¹H NMR (270 MHz, CH₃OH-d₄) δ ppm 8.04 (d, J=6.60 Hz, 1H)7.77-7.75/m, 2H) 6.85-6.83 (m, 2H) 6.68-6.83 (m, 1H) 3.87-3.85 (m, 4H)3.77-3.75 (m, 6H) 3.49-3.45 (m, 4H) 2.65 (s, 1H); LC-MS 435 (M−H)⁺;Purity (HPLC) 98%.

EXAMPLE 66

[0792]N-(4-Bromo-2-methylphenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamideHydrochloride

[0793] The synthesis was preformed essentially as described in MethodH-L. Yield: 12.2 mg (5.3%).

[0794]¹H NMR (270 MHz, CH₃OH-d₄) δ ppm 8.07 (d, J=6.33 Hz, 1H) 7.86-7.79(m, 2H) 7.40 (d, J=1.58 Hz, 1H) 7.30-7.29 (m, 1H) 7.08 (d, J=8.71 Hz,1H) 3.96-3.92 (m, 4H) 3.53-3.51 (4H) 2.66 (s, 1H) 2.11 (s, 3H); LC-MS467 (M−H)⁺; Purity (HPLC) 90%.

EXAMPLE 67

[0795]2-(4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonyl)-1,2,3,4-tetrahydro-isoquinolineHydrochloride

[0796] The synthesis was preformed essentially as described in MethodH-L from4-[2-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-thieno[3,2-c]pyridin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (0.235 mmol, 1 equiv.). Yield: 4.0 mg. LC/MS:t_(R)=0.801 (System: 30% to 60% ACN in 1.5 min, Hypersil BDS), Purity:92%. MS: 415 (M+1) ¹H NMR (270 MHz, DMSO-d₆) δ ppm 2.87 (t, J=5.81 Hz,2H) 3.30 (s, 4H) 4.43 (s, 2H) 7.15 (m, 4H) 7.70 (d, J=5.54 Hz, 1H) 8.12(s, 1H) 8.18 (d, J=5.54 Hz, 1H) 6 aliphatic protons were obscured by thewater-peak in the spectra and so could not be analyzed.

EXAMPLE 68

[0797] 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic Acid(2-thiophen-2-yl-ethyl)-amide Hydrochloride

[0798] The synthesis was preformed essentially as described in MethodH-L from4-[2-(2-thiophen-2-yl-ethylsulfamoyl)-thieno[3,2-c]pyridin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (0.235 mmol, 1 equiv.). Yield: 8.7 mg. LC/MS:t_(R)=0.430 (System: 30% to 60% ACN in 1.5 min, Hypersil BDS), Purity:93%. MS: 409 (M+1) ¹H NMR (270 MHz, DMSO-d₆) δ ppm 2.25 (s, 1H) 2.75 (s,1H) 2.96 (t, J=6.99 Hz, 1H) 3.16 (q, J=6.51 Hz, 1H) 3.31 (s, 4H) 3.70(s, 4H) 6.90 (m, 1H) 7.32 (t, J=5.54 Hz, 1H) 7.70 (d, J=5.81 Hz, 1H)8.04 (d, J=1.85 Hz, 1H) 8.18 (d, J=5.54 Hz, 1H) 8.36 (m, 1H) 9.05 (s,1H).

EXAMPLE 69

[0799] 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic Acid(4-chloro-2,5-dimethoxy-phenyl)amide Hydrochloride

[0800] The synthesis was preformed essentially as described in MethodH-L from4-[2-(4-chloro-2,5-dimethoxy-phenylsulfamoyl)-thieno[3,2-c]pyridin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (0.112 mmol, 1 equiv.) was used as thethienopyridine in Method C. Yield: 14.7 mg. LC/MS: t_(R)=0.610 (System:30% to 60% ACN in 1.5 min, YMC), Purity: 92%. MS: 469 (M+1) ¹H NMR (270MHz, DMSO-d₆) δ ppm 3.17 (s, 1H) 3.27 (s, 4H) 3.38 (s, 3H) 3.58 (d,J=4.22 Hz, 4H) 3.77 (s, 3H) 7.08 (s, 1H) 7.69 (d, J=5.81 Hz, 1H) 7.81(s, 1H) 8.16 (d, J=5.81 Hz, 1H) 9.07 (s, 1H) 10.17 (s, 1H).

EXAMPLE 70

[0801] 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic Acidphenethyl-amide Hydrochloride

[0802] The synthesis was preformed essentially as described in MethodH-L from4-(2-phenethylsulfamoyl-thieno[3,2-c]pyridin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester (0.112 mmol, 1 equiv.). Yield: 3.8 mg. LC/MS:t_(R)=0.410 (System: 30% to 60% ACN in 1.5 min, YMC), Purity: 91%. MS:403 (M+1) ¹H NMR (270 MHz, CH₃OH-d₄) δ ppm 1.44 (d, J=7.13 Hz, 2H) 3.51(d, J=4.75 Hz, 4H) 3.54 (s, 2H) 3.94 (m, 4H) 7.05 (m, 4H) 7.16 (m, 1H)7.62 (s, 1H) 7.72 (d, J=6.60 Hz, 1H) 8.00 (d, J=6.60 Hz, 1H).

EXAMPLE 71

[0803] 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic Acid(2,6-diethyl-phenyl)-amide Hydrochloride

[0804] The synthesis was preformed essentially as described in MethodH-L from4-[2-(2,6-dethylphenylsulfamoyl)-thieno[3,2-c]pyridin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (0.112 mmol, 1 equiv.). Yield: 9.0 mg. LC/MS:t_(R)=0.830 (System: 30% to 60% ACN in 1.5 min, YMC), Purity: 92%. MS:431 (M+1) ¹H NMR (270 MHz, DMSO-D6) δ ppm 0.96 (t, J=7.52 Hz, 6H) 2.25(m, 1H) 2.43 (s, 2H) 2.75 (t, J=1.72 Hz, 1H) 3.26 (s, 4H) 3.62 (s, 4H)7.09 (s, 1H) 7.12 (s, 1H) 7.23 (m, 1H) 7.73 (d, J=5.81 Hz, 1H) 7.77 (s,1H) 8.19 (d, J=5.81 Hz, 1H) 9.04 (s, 1H) 9.95 (s, 1H).

EXAMPLE 72

[0805] 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic Acid(3-phenyl-propyl)-amide Hydrochloride

[0806] The synthesis was preformed essentially as described in MethodH-L from4-[2-(3-phenylpropylsulfamoyl)-thieno[3,2-c]pyridin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (0.112 mmol, 1 equiv.). Yield: 13.0 mg. LC/MS:t_(R)=0.726 (System: 30% to 60% ACN in 1.5 min, YMC), Purity: 91%. MS:417 (M+1) ¹H NMR (270 MHz, CH₃OH-d₄) δ ppm 1.82 (m, 2H) 2.63 (m, 2H)3.04 (t, J=6.86 Hz, 2H) 3.55 (s, 4H) 4.09 (s, 4H) 7.16 (m, 4H) 7.82 (d,J=6.60 Hz, 1H) 8.05 (d, J=6.33 Hz, 1H) 8.14 (s, 1H).

EXAMPLE 73

[0807] 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic Acid(3,3-diphenyl-propyl)-amide Hydrochloric Acid

[0808] The synthesis was preformed essentially as described in MethodH-L from4-[2-(3,3-diphenylpropylsulfamoyl)-thieno[3,2-c]pyridin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (0.112 mmol, 1 equiv.). Yield: 14.4 mg. LC/MS:t_(R) 1.109 (System: 30% to 60% ACN in 1.5 min, YMC), Purity: 93%. MS:493 (M+1) ¹H NMR (270 MHz, DMSO-d₆) δ ppm 2.20 (m, 2H) 2.80 (m, 2H) 3.29(s, 4H) 3.67 (d, J=5.01 Hz, 4H) 4.01 (m, 1H) 7.14 (m, 8H) 7.71 (d,J=5.81 Hz, 1H) 7.95 (s, 1H) 8.18 (d, J=5.81 Hz, 1H) 8.27 (m, 2H) 9.13(s, 2H).

EXAMPLE 74

[0809] 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic Acid[2-(5-methoxy-1H-indol-3-yl)ethyl]-amide Hydrochloride

[0810] The synthesis was preformed essentially as described in MethodH-L from4-{2-[2-(5-methoxy-1H-indol-3-yl)-ethylsulfamoyl]-thieno[3,2-c]pyridin-4-yl}-piperazine-1-carboxylicacid tert-butyl ester (0.112 mmol, 1 equiv.). Yield: 6.1 mg. LC/MS:t_(R)=0.364 (System: 30% to 60% ACN in 1.5 min, YMC), Purity: 91%. MS:472 (M+1) ¹H NMR (270 MHz, CH₃OH-d₄) δ ppm 2.85 (t, J=6.20 Hz, 2H) 3.48(t, J=6.20 Hz, 2H) 3.55 (m, 4H) 3.80 (s, 3H) 4.02 (m, 4H) 6.44 (dd,J=8.71, 2.37 Hz, 1H) 6.80 (m, 2H) 6.97 (s, 1H) 7.64 (s, 1H) 7.67 (s, 1H)7.97 (d, J=6.60 Hz, 1H).

EXAMPLE 75

[0811] 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic Acid4-trifluoromethyl-benzylamide Hydrochloride

[0812] The synthesis was preformed essentially as described in MethodH-L from4-[2-(4-trifluoromethyl-benzylsulfamoyl)-thieno[3,2-c]pyridin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (0.112 mmol, 1 equiv.) was used as thethienopyridine in Method C. Yield: 1.9 mg. LC/MS: t_(R)=0.771 (System:30% to 60% ACN in 1.5 min, YMC), Purity: 91%. MS: 457 (M+1) ¹H NMR (270MHz, CH₃OH-d₄) δ ppm 3.54 (m, 4H) 3.98 (m, 4H) 4.36 (s, 2H) 7.49 (m, 4H)7.74 (d, J=6.86 Hz, 1H) 8.02 (s, 1H) 8.07 (d, J=6.60 Hz, 1H).

EXAMPLE 76

[0813] 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic Acidbenzyl-ethyl-amide Hydrochloride

[0814] The synthesis was preformed essentially as described in MethodH-L from4-[2-(benzyl-ethyl-sulfamoyl)-thieno[3,2-c]pyridin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (0.112 mmol, 1 equiv.). Yield: 6.4 mg. LC/MS:t_(R)=0.930 (System: 30% to 60% ACN in 1.5 min, YMC), Purity: 95%. MS:417 (M+1) ¹H NMR (270 MHz, CH₃OH-d₄) δ ppm 1.03 (t, J=7.13 Hz, 3H) 3.37(m, 2H) 3.57 (s, 2H) 3.75 (m, 2H) 4.11 (s, 2H) 4.50 (s, 2H) 5.80 (s, 1H)7.32 (m, 5H) 7.84 (d, J=6.60 Hz, 1H) 8.07 (d, J=6.60 Hz, 1H) 8.14 (s,1H).

[0815] Intermediate 55

[0816]tert-Butyl-4-(3-{[(3-ethylphenyl)amino]sulfonyl}thieno[3,2-c]pyridin-4-yl)piperazine-1-carboxylate

[0817] Prepared from tert-butyl4-[3-(chlorosulfonyl)thieno[3,2-c]pyridin-4-yl]piperazine-1-carboxylate(90.0 mg, 0.215 mmol) and 3-ethylaniline (33.9 mg, 0.28 mmol) to givethe title compound as an off-white solid (82.7 mg, 76%). ¹H NMR (400MHz, CDCl₃) δ 1.03 (t, J=7.5 Hz, 3H), 1.48 (s, 9H), 2.47 (q, J=7.7 Hz,2H), 3.00-3.53 (m, 6H), 4.02-4.44 (m, 2H), 6.66 (d, J=8.0 Hz, 1H), 6.75(s, 1H), 6.66 (d, J=8.0 Hz, 1H), 7.02 (t, J=7.8 Hz, 1H), 7.67 (d, J=5.5Hz, 1H), 8.24 (s, 1H), 8.39 (d, J=5.5 Hz, 1H), 9.80 (s, 1H). MS (ESI+)m/z 503.2 (M+H)⁺. HPLC 97%, R_(T): 3.93 min (5-99% MeCN over 3 min).

EXAMPLE 77

[0818]N-(3-Ethylphenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-3-sulfonamideHydrochloride

[0819] Prepared from tert-butyl4-(3-{[(3-ethylphenyl)amino]sulfonyl}thieno[3,2-c]pyridin-4-yl)piperazine-1-carboxylate(81.1 mg, 0.161 mmol) which afforded 19 mg (98%) of the product as awhite solid (38.0 mg, 54%). ¹H NMR (400 MHz, CH₃OH-d₄) δ 1.09 (t, J=7.5Hz, 3H), 2.51 (q, J=7.5 Hz, 2H), 3.59 (br.s, 8H), 6.89-6.92 (m, 3H),7.12-7.14 (m, 1H), 8.06 (d, J=6.0 Hz, 1H), 8.36 (d, J=6.0 Hz, 1H), 8.49(s, 1H). MS (ESI+) m/z 403.2 (M+H)⁺. HPLC 95%, R_(T): 3.02 min (5-99%MeCN over 3 min).

[0820] Intermediate 56

[0821] tert-Butyl4-(3-bromothieno[3,2-c]pyridin-4-yl)piperazine-1-carboxylate

[0822] A mixture of 3-bromo-4-chlorothieno[3,2-c]pyridine (729 mg, 2.93mmol), tert-butyl piperazine-1-carboxylate (1.64 g, 8.80 mmol) and K₂CO₃(811 mg, 5.87 mmol) in DMSO (45 mL) was stirred for 5 days at 100° C.After addition of H₂O and ethyl acetate, the layers were separated. Thewater phase was extracted twice with ethyl acetate, and the combinedorganic phases were washed with water and brine and dried (MgSO₄). Afterfiltration and removal of the solvent, the residue was purified bysilica gel flash chromatography (pentane/ethyl acetate, 8:2) to give theproduct as a white powder (398 mg, 34%). HPLC 99%, R_(T): 3.27 min(5-99% MeCN over 3 min). ¹H NMR (400 MHz, CH₃OH-d₄) δ 1.48 (s, 9H), 3.21(br.s, 4H), 3.71 (s br., 4H), 7.61 (d, J=6.1 Hz, 1H), 7.72 (s, 1H), 8.08(d, J=5.6 Hz, 1H). MS (ESI+) m/z 398.2 (M+H)⁺.

[0823] Intermediate 57

[0824]{4-[4-(tert-Butoxycarbonyl)piperazin-1-yl]thieno[3,2-c]pyridin-3-yl}sulfonyl)lithium

[0825] To a suspension of tert-Butyl4-(3-bromothieno[3,2-c]pyridin-4-yl)piperazine-1-carboxylate (4.055 g,10.18 mmol) in diethyl ether (30 mL) at −78° C. under N₂ atmosphere wasadded dropwise an 1.6 M solution of n-BuLi in hexanes (9.5 mL, 15.2mmol). After 1 h of stirring, a saturated solution of SO₂ in THF (25 mL)at −78° C. was transferred via a cannula to the mixture. The reactionwas allowed to gradually increase to ambient temperature over night. Thesolvent was evaporated, and the residue was washed with several portionsof diethyl ether and then dried under vacuum to give 4.094 g of anoff-white solid consisting of 66% of the title compound and 34% of(n-butylsulfonyl)lithium as by-product. This mixture was used withoutany further purification in the next step. ¹H NMR (400 MHz, CH₃OH-d₄) δ1.48 (s, 9H), 3.22 (br.s, 4H), 3.72 (s br., 4H), 7.60 (d, J=5.5 Hz, 1H),8.06 (d, J=5.5 Hz, 1H), 8.14 (s, 1H). MS (ESI+) m/z 384.0 (M+H)⁺. HPLCR_(T): 2.62 min (5-99% MeCN over 3 min).

[0826] Intermediate 58

[0827]tert-Butyl-4-[3-(chlorosulfonyl)thieno[3,2-c]pyridin-4-yl]piperazine-1-carboxylate

[0828] To a suspension of({4-[4-(tert-butoxycarbonyl)piperazin-1-yl]thieno[3,2-c]pyridin-3-yl}sulfonyl)lithium(2.751 g, 7.06 mmol (3.126 g of the crude product mixture)) in DCM (40mL) at 0° C. was added N-chlorosuccinimide (1.338 g, 10.0 mmol). After20 minutes, the temperature was raised to ambient, and the reactionmixture was stirred for an additional 2.5 h. The resulting productsolution was washed with water, and the water phase was extracted withDCM. The combined organic extracts were washed with brine and dried overMgSO₄. After filtration and evaporation of the solvent, the residue waswashed with several portions of pentane to yield the product as anoff-white solid (2.024 g, 69%). ¹H NMR (400 MHz, CH₃OH-d₄) δ 1.47 (s,9H), 3.11 (br.s, 4H), 3.2-4.3 (s br., 4H), 7.68 (d, J=5.5 Hz, 1H), 8.45(d, J=5.5 Hz, 1H), 8.60 (s, 1H). MS (ESI+) m/z 418.2 (M+H)⁺. HPLC 92%,R_(T): 3.76 min (5-99% MeCN over 3 min).

[0829] Intermediate 59

[0830]tert-Butyl-4-(3-{[(4-isopropylphenyl)amino]sulfonyl}thieno[3,2-c]pyridin-4-yl)piperazine-1-carboxylate

[0831] Prepared from tert-butyl4-[3-(chlorosulfonyl)thieno[3,2-c]pyridin-4-yl]piperazine-1-carboxylate(90.0 mg, 0.215 mmol) and 4-isopropylaniline (37.9 mg, 0.28 mmol) togive the title compound as an off-white solid (58.3 mg, 52%). ¹H NMR(400 MHz, CDCl₃) δ 1.12 (d, J=7.0 Hz, 6H), 1.47 (s, 9H), 2.76 (sept.,J=6.9 Hz, 2H), 3.01-3.53 (m, 6H), 4.04-4.41 (m, 2H), 6.79 (d, J=8.5 Hz,2H), 6.66 (d, J=8.5 Hz, 2H), 7.69 (d, J=5.5 Hz, 1H), 8.23 (s, 1H), 8.40(d, J=5.5 Hz, 1H), 9.90 (s, 1H). MS (ESI+) m/z 517.2 (M+H)⁺. HPLC 97%,R_(T): 4.01 min (5-99% MeCN over 3 min).

EXAMPLE 78

[0832]N-(4-Isopropylphenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-3-sulfonamideHydrochloride

[0833] Prepared from tert-butyl4-(3-{[(4-isopropylphenyl)amino]sulfonyl}thieno[3,2-c]pyridin-4-yl)piperazine-1-carboxylate(60.0 mg, 0.116 mmol) which afforded 19 mg (98%) of the product as awhite solid (25.8 mg, 49%) according to Method H-L. ¹H NMR (400 MHz,CH₃OH-d₄) δ 1.16 (d, J=7.0 Hz, 6H), 2.81 (sept., J=6.8 Hz, 1H), 3.59 (s,br., 8H), 7.00 (d, J=8.0 Hz, 2H), 7.10 (d, J=8.0 Hz, 2H), 8.07 (s, br.,1H), 8.37 (s, br., 1H), 8.50 (s, 1H). MS (ESI+) m/z 417.2 (M+H)⁺. HPLC94%, R_(T): 3.14 min (5-99% MeCN over 3 min).

EXAMPLE 79

[0834]N-(4-Methylphenyl)-4-(pyrrolidin-3-yloxy)thieno[3,2-c]pyridine-2-sulfonamideHydrochloride

[0835] 4-Chloro-N-(4-methylphenyl)thieno[3,2-c]pyridine-2-sulfonamide(60.0 mg, 0.17 mmol) in dry DMF (1 mL) and NaH (5.1 mg, 0.21 mmol) wasadded to pyrrolidin-3-ol (18.5 mg, 0.21 mmol) under nitrogen. Themixture was heated in the microwave at 200° C. in 5 min. The product waspurified by preparative HPLC. Yield: 29.9 mg (43.4%). ¹H NMR (270 MHz,CH₃OH-d4) δ ppm 8.09 (s, 1H) 7.71 (d, J=6.93 Hz, 1H) 7.46 (d, J=6.93 Hz,1H) 7.47-7.44 (m, 4H) 4.67 (d, J=3.22 Hz, 1H) 3.97 (s, 2H) 2.26 (s, 3H).LC-MS 390 (M−H)⁺; Purity (HPLC) 99%.

EXAMPLE 80

[0836]N-(4-Methylphenyl)-4-(piperidin-4-yloxy)thieno[3,2-c]pyridine-2-sulfonamideHydrochloride

[0837] The synthesis was preformed essentially as described for compoundofN-(4-methylphenyl)-4-(pyrrolidin-3-yloxy)thieno[3,2-c]pyridine-2-sulfonamidehydrochloride. Yield: 16.2 mg (22.7%). ¹H NMR (270 MHz, CH₃OH-d₄) δ ppm7.81-7.78 (m, 2H) 7.62 (d, J=6.93 Hz, 1H) 7.13-7.04 (m, 4H) 4.05-3.94(m, 1H) 3.90-3.88 (m, 2H) 3.63-3.58 (m, 2H), 2.27 (s, 3H) 2.06-2.03 (m,2H) 2.01-1.71 (m, 2H); LC-MS 404 (M−H)⁺; Purity (HPLC) 99%.

EXAMPLE 81

[0838]N-(2,3-Difluorobenzyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamideHydrochloride

[0839] Yield: 74.4 mg (39.2%). ¹H NMR (270 MHz, CH₃OH-d₄) δ ppm8.10-8.03 (m, 2H) 7.81 (d, J=6.68 Hz, 1H) 7.16-7.05 (m, 3H) 4.37 (s, 2H)4.11-4.07 (m, 4H) 3.59-3.53 (m, 4H); LC-MS 425 (M−H)⁺; Purity (HPLC)90%.

EXAMPLE 82

[0840]N-(3-Chlorobenzyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamideHydrochloride

[0841] Yield: 74.4 mg (44.7%). ¹H NMR (270 MHz, CH₃OH-d₄) δ ppm8.04-8.01 7.85 (d, J=6.93 Hz, 1 H) 7.22-7.15 (m, 4H) 4.30 (s, 2H)4.14-4.10 (m, 4H) 3.60-3.54 (m, 4H); LC-MS 423(M−H)⁺; Purity (HPLC) 90%.TABLE 5

EXAMPLE R² R⁴ 834-(1,4-Diazepan-1-yl)-2-(phenylsulfonyl)thieno[3,2-c]pyridinehydrochloride

84 4-(1,4-Diazepan-1-yl)-2-[(3,4-dichlorophenyl)sulfonyl]thieno[3,2-c]pyridine hydrochloride

85 4-(1,4-Diazepan-1-yl)-2-[1-naphthylsulfonyl)thieno[3,2-c]pyridinehydrochloride

86 4-(1,4-Diazepan-1-yl)-2-[4-tert-butylphenylsulfonyl)thieno[3,2-c]pyridine hydrochloride

87 4-(1,4-Diazepan-1-yl)-2-[3,4-dimethylphenylsulfonyl)thieno[3,2-c]pyridine hydrochloride

88 2-[(4-Bromophenyl)sulfonyl]-4-(1,4-diazepan-1-yl)thieno[3,2-c]pyridine hydrochloride

89 2-(Phenylsulfonyl)-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride

90 2-(3-Methoxy-benzenesulfonyl)-4-piperazin-1-yl-thieno[3,2- c]pyridinehydrochloride

91 2-(4-Methoxy-benzenesulfonyl)-4-piperazin-1-yl-thieno[3,2- c]pyridinehydrochloride

92 4-piperazin-1-yl-2-{[4-trifluoromethyl)phenyl]sulfonyl}thieno[3,2-c]pyridine hydrochloride

93 2-[[2-tert-Butylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride

94 2-[(3,4-Dichlorophenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride

95 2-[(4-tert-Butylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride

96 2-(1-Naphthyl sulfonyl)-4-piperazin-1-ylthieno[3,2-e]pyridinehydrochloride

97 2-[(3-Fluorophenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride

98 2-(Mesitylsulfonyl)-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride

99 2-[(2-Methoxyphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride

100 2-[(2,4-Dimethoxyphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride

101 2-[(2,4-Dimethylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride

102 2-[(2,5-Dimethylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride

103 2-[(2-Ethylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride

104 4-(Piperazinyl)-2-(3-methoxybenzyl-sulfonyl)-thienopyridinehydrochloride

105 2-(Benzylsulfonyl)-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride

106 4-Piperazin-1-yl-2-{[4-(trifluoromethyl)benzyl]sulfonyl}thieno[3,2-c]pyridine hydrochloride

107 2-[(3-Bromobenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride

108 2-[(2,3-Difluorobenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride

109 2-[(4-Bromobenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride

110 2-{[2,5-bis(Trifluoromethyl)benzyl]sulfonyl}-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride

111 2-[(4-Methylbenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride

112 2-{[5-Chloro-2-(trifluoromethyl)benzyl]sulfonyl}-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride

113 2-[(3,5-Dimethoxybenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride

114 2-[(2-Naphthylmethyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride

115 4-Piperazin-1-yl-2-{[4-(1,2,3-thiadiazol-5-yl)benzyl]sulfonyl}thieno[3,2-c]pyridine hydrochloride

116 1-(4-Pyrrolidin-1-ylphenyl)-2-[(4-piperazine-1-ylthieno{3,2-c]pyridin-2-yl) sulfonyl] propanone hydrochloride

117 1-[4-(Diethylamino)phenyl]-2-[(4-piperazine-1-ylthieno[3,2-c]pyridin-2-yl) sulfonyl] propanone hydrochloride

118 1-(4-Bromophenyl)-2-[(4-piperazin-1-ylthieno[3,2-c]pyridin-2-yl)sulfonyl] propanone

119 1-(3-Methoxyphenyl)-2-[(4-piperazin-1-ylthieno[3,2-c]pyridin-2-yl)sulfonyl] propanone

120 1-Phenyl-2-[(4-piperazin-1-ylthieno[3,2-c]pyridin-2-yl)sulfonyl]propanone

[0842]

[0843] Intermediate 60

[0844] tert-Butyl4-(2-bromothieno[3,2-c]pyridin-4-yl)piperazine-1-carboxylate

[0845] 2-Bromo-4-chlorothieno[3,2-c]pyridine (5.0 g, 20.24 mmol) andK₂CO₃ (13.97 g, 101.2 mmol) was stirred in DMSO (20 mL) followed byaddintion of tert-butyl piperazine-1-carboxylate (4.14 g, 22.26 mmol).The reaction mixture was stirred at 100° C. for 6 days. The reactionmixture was filtered to eliminate the carbonate and addition of water(50 mL) and ethyl was followed. The phases were separated and theaqueous phase was extracted with ethyl acetate. The combined organicphases were dried (MgSO₄) and the solvent was evaporated. The crudeproduct was purified by flash chromatography using ethyl acetate/hexanes(2/8) as eluent to give 2 g of the desired product, yield 25%, 99% pure.¹H NMR (270 MHz, CDCl₃) δ 1.48 (s, 9H), 1.52-1.63 (m, 1H), 3.42-3.47 (m,4H), 3.61-3.64 (m, 4H), 7.22 (dd, J=5.4, 1 Hz, 1H), 7.35 (d, J=1 Hz,1H), 8.04 (d, J=5.4 Hz, 1H). m/z=398.91 (M+H), bromide pattern.

[0846] Intermediate 61

[0847] tert-butyl4-(2-bromothieno[3,2-c]pyridin-4-yl)-1,4-diazepane-1-carboxylate

[0848] The same procedure above intermediate was used starting from2-bromo-4-chlorothieno[3,2-c]pyridine (7.5 g, 30.45 mmol), K₂CO₃ (6.7 g,33.5 mmol) and tert-butyl 1,4-diazepane-1-carboxylate (21.0 g, 152.2mmol) in DMSO (30 mL). Purification by flash chromatography 3.04 g ofthe title compound (Yield 25%). HPLC purity 92%; ¹H NMR (270 MHz, CDCl₃)δ 1.38 (s, 4.5H), 1.43 (s, 4.5H), 1.96-2.11 (m, 2H), 3.36-3.41 (m, 1H),3.46-3.51 (m, 1H), 3.65-3.87 (m, 6H), 7.02-7.04 (m, 1H), 7.40-7.42 (m,1H), 7.94 (d, J=5.4 Hz, 1H). m/z=411.97 (M+H).

[0849] Coupling with Thiophenols (Method M)

[0850] Intermediate 62

[0851] tert-butyl4-(2-phenylthio)thieno[3,2-c]pyridin-4-yl)-1,4-diazepane-1-carboxylate

[0852] tert-Butyl4-(2-bromothieno[3,2-c]pyridin-4-yl)-1,4-diazepane-1-carboxylate (0.31g, 0.752 mmol), pulverized KOH (0.084 g, 1.5 mmol) and Cu₂(I)O (0.1 g,0.75 mmol) was mixed with DMF (1 mL) before the addition of a solutionof benzenethiol (0.016 g, 1.5 mmol) in DMF (1 mL). The reaction mixturewas heated to 120° C. for 15 h. The reaction mixture was poured in asilica plug and eluted with chloroform, to give the crude product. Thecrude product was purified by flash chromatography using ethylacetate/hexanes (2/8) as eluent to give 0.21 g of the desired product,yield 64%, 90% pure. ¹H NMR (270 MHz, CDCl₃) δ 1.37 (s, 4.5H), 1.43 (s,4.5H), 1.97-2.10 (m, 2H), 3.36-3.43 (m, 1H), 3.46-3.53 (m, 1H),3.64-3.73 (m, 2H), 3.78-3.96 (m, 4H), 7.05 (d, J=5.4 Hz, 1H), 7.22-7.32(m, 5H), 7.59-7.63 (m, 1H), 7.97 (d, J=5.4 Hz, 1H). m/z=442.15 (M+H).

[0853] Oxidation of Thio-Derivatives (Method N)

[0854] Intermediate 63

[0855] tert-Butyl4-(2-phenylsulfonyl)thieno[3,2-c]pyridin-4-yl)-1,4-diazepane-1-carboxylateA solution of tert-Butyl4-(2-phenylthio)thieno[3,2-c]pyridin-4-yl)-1,4-diazepane-1-carboxylate(0.21 g, 0.48 mmol) and NaOAc (0.5 g) in ethanol (10 mL), (pH ˜5)followed by the addition of Oxone (0.64 g, 1.04 mmol) dissolved in water(1 mL). The reaction mixture was stirred at RT for 16 h. AdditionalOxone (0.32 g) in water (1 mL) was added. Full conversion of the SM wasobtained after 8 h. Water (50 mL) and chloroform (30 mL) were added. Thephases were separated and the aqueous phase was extracted withchloroform. The combined organic phases were dried over (MgSO₄), thesolvent was evaporated to give the crude product which was purified byreverse-phase chromatography (10→90), to give 0.191 g of the desiredproduct as yellow oil (Yield 86%) 98% pure. ¹H NMR (270 MHz, CDCl₃) δ1.28 (s, 4.5H), 1.38 (s, 4.5H), 1.99-2.03 (m, 2H), 3.31-3.40 (m, 1H),3.42-3.47 (m, 1H), 3.63-3.69 (m, 2H), 3.85-3.98 (m, 4H), 7.02 (d, J=5.4Hz, 1H), 7.48-7.61 (m, 3H), 7.76-8.01 (m, 3H), 8.06-8.08 (m, 1H). m/z474.01 (M+H).

[0856] Removal of the t-butyl-carboxylate Protecting Group (Method O)

EXAMPLE 83

[0857] 4-(1,4-Diazepan-1-yl)-2-(phenylsulfonyl)thieno[3,2-c]pyridineHydrochloride

[0858] tert-Butyl4-(2-phenylsulfonyl)thieno[3,2-c]pyridin-4-yl)-1,4-diazepane-1-carboxylate(0.165 g, 0.348 mmol) was dissolved in DCM (2 mL) and TFA (1 mL) wasadded. The reaction mixture was stirred for 2 h. The solvent wasevaporated. Methanol and HCl in ether was added (×3) to give 0.118 g ofthe desired HCl salt, yield 85%, 98% pure. ¹H NMR (270 MHz, CHOH-d₄) δ2.45-2.52 (m, 2H), 3.45-3.52 (m, 2H), 3.70-3.79 (m, 2H), 4.18-4.22 (m,2H), 4.30-4.40 (m, 2H), 7.62-7.76 (m, 5H), 7.91 (d, J=5.4 Hz, 1H), 8.11(dd, J=5.4, 1 Hz, 1H), 8.41 (d, J=1 Hz, 1H). m/z=374.09 (M+H−HCl).

[0859] Intermediate 64

[0860] tert-Butyl4-[2-(4-tert-butylphenyl)thio]thieno[3,2-c]pyridin-4-yl)-1,4-diazepane-1-carboxylate

[0861] The product was prepared according to Method M. Purification byflash chromatography using ethyl acetate/hexanes (2/8) as eluent gave0.035 g, 99% pure. ¹H NMR (270 MHz, CDCl₃) δ 1.28 (s, 9H), 1.38 (s,4.5H), 1.43 (s, 4.5H), 1.98-2.03 (m, 2H), 3.35-3.41 (m, 1H), 3.46-3.52(m, 1H), 3.62-3.72 (m, 2H), 3.77-3.93 (4H), 7.04 (d, J=5.4 Hz, 1H),7.27-7.34 (m, 4H), 7.54-7.56 (m, 1H), 7.95 (d, J=5.4 Hz, 1H). m/z=498.0(M+H).

[0862] Intermediate 65

[0863] tert-Butyl4-[2-(4-tert-butylphenyl)sulfonyl]thieno[3,2-c]pyridin-4-yl)-1,4-diazepane-1-carboxylate

[0864] Procedure B from tert-butyl4-[2-(4-tert-butylphenyl)thio]thieno[3,2-c]pyridin-4-yl)-1,4-diazepane-1-carboxylate(0.035 g, 0.070 mmol), Oxone (0.17 g, 0.28 mmol), NaOAc (0.5 g) in EtOH(2 mL followed by reversed phase chromatography (40→70), gave 6 mg ofthe product. Yield 17%, 98% pure. ¹H NMR (270 MHz, CDCl₃) δ 1.32 (s,9H), 1.35 (s, 9H), 2.05-2.15 (m, 2H), 3.45-3.62 (m, 2H), 3.75-4.13 (m,6H), 7.20-7.27 (m, 5H), 7.58 (d, J=10.8 Hz, 1H), 7.93 (d, J=10.8 Hz,1H). m/z=530.0 (M+H).

[0865] Intermediate 66

[0866] tert-Butyl4-[2-(3,4-dimethylphenyl)thio]thieno[3,2-c]pyridin-4-yl)-1,4-diazepane-1-carboxylate

[0867] The title compound was obtained according to Method M.Purification by flash chromatography using ethyl acetate/hexanes (2/8)as eluent gave 0.022 g, 95% pure. ¹H NMR (270 MHz, CDCl₃) δ 1.38 (s,4.5H), 1.43 (s, 4.5H), 1.96-2.04 (m, 2H), 2.21 (s, 3H), 2.22 (s, 3H),3.37-3.45 (m, 2H), 3.47-3.50 (m, 2H), 3.77-3.95 (m, 4H), 7.01-7.12 (m,3H), 7.16 (s, 1H), 7.53 (dd, J=5.4, 1 Hz, 1H), 7.94 (d, J=5.4 Hz, 1H).m/z=470.3 (M+H).

[0868] Intermediate 67

[0869] tert-Butyl4-[2-(3,4-dimethylphenyl)sulfonyl]thieno[3,2-c]pyridin-4-yl)-1,4-diazepane-1-carboxylate

[0870] Procedure B from tert-Butyl4-[2-(3,4-dimethylphenyl)thio]thieno[3,2-c]pyridin-4-yl)-1,4-diazepane-1-carboxylate(0.022 g, 0.047 mmol); OXONE (0.11 g, 0.19 mmol); NaOAc (0.5 g) in EtOH(2 mL) followed by reversed phase chromatography (40→70), 9 mg of theproduct. Yield 38%, 92% pure. ¹H NMR (270 MHz, CDCl₃) δ 1.35 (s, 9H),2.08-2.20 (m, 2H), 2.33 (s, 6H), 3.52-3.59 (m, 2H), 3.83-3.88 (m, 2H),4.08-4.18 (m, 4H), 7.21-7.28 (m, 2H), 7.31-7.35 (m, 1H), 7.73-7.75 (m,2H), 8.02 (d, J=5.4 Hz, 1H). m/z=502.21 (M+H).

[0871] Intermediate 68

[0872] tert-Butyl4-[2-(1-naphthyl)thio]thieno[3,2-c]pyridin-4-yl)-1,4-diazepane-1-carboxylate

[0873] The title compound was obtained according to Method M.Purification by flash chromatography using ethyl acetate/hexanes (2/8)as eluent gave 0.055 g. HPLC purity 99%;

[0874]¹H NMR (270 MHz, CDCl₃) δ 1.37 (s, 4.5H), 1.43 (s, 4.5H),1.89-2.20 (m, 2H), 3.30-3.40 (m, 1H), 3.43-3.50 (m, 1H), 3.60.3.90 (m,6H), 6.99 (d, J=5.4 Hz, 1H), 7.39 (dd, J=8.1, 1 Hz, 1H), 7.50-7.61 (m,5H), 7.79-7.88 (m, 2H), 7.92 (d, J=5.4 Hz, 1H), 8.40-8.44 (m, 1H). m/z498.26 (M+H).

[0875] Intermediate 69

[0876] tert-Butyl4-[2-(1-naphthyl)sulfonyl]thieno[3,2-c]pyridin-4-yl)-1,4-diazepane-1-carboxylate

[0877] Procedure B from tert-Butyl4-[2-(1-naphthyl)thio]thieno[3,2-c]pyridin-4-yl)-1,4-diazepane-1-carboxylate(0.055 g, 0.112 mmol); Oxone (0.27 g, 0.448 mmol); NaOAc (0.5 g) in EtOH(2 mL) followed reversed phase chromatography (40→70) gave 15 mg of theproduct. Yield 26%, 93% pure. ¹H NMR (270 MHz, CDCl₃) δ 1.34 (s, 9H),2.06-2.10 (m, 2H), 3.48-3.62 (m, 2H), 3.78-3.86 (m, 2H), 3.95-4.16 (m,4H), 7.19-7.31 (m, 2H), 7.60-7.75 (m, 3H), 7.92-7.99 (m, 2H), 8.18 (m,J=8.1 Hz, 1H), 8.50-8.53 (m, 1H), 8.77-8.80 (m, 1H). m/z=524.22 (M+H);

EXAMPLE 84

[0878]4-(1,4-Diazepan-1-yl)-2-[(3,4-dichlorophenyl)sulfonyl]thieno[3,2-c]pyridineHydrochloride

[0879] tert-Butyl4-{2-[(3,4-dichlorophenyl)sulfonyl]thieno[3,2-c]pyridin-4-yl}-1,4-diazepane-1-carboxylatewas prepared from 3,4-dichlorothiophenol (60 mg, 15%), as a beige solid,by the application of the general procedures A and B described above. ¹HNMR (CDCl₃) δ 8.27-8.14 (m, 1H), 8.11-8.04 (m, 2H), 7.87-7.80 (m, 1H),7.67-7.62 (m, 1H), 7.26-7.20 (m, 1H), 4.18-3.98 (m, 4H), 3.87-3.74 (m,2H), 3.61-3.44 (m, 2H), 2.20-2.00 (m, 2H), 1.33 (s, 9H); MS m/z 542(M+1). The title compound (50 mg, 95%) was obtained as a beige solid, bythe application of the general procedure C described above. ¹H NMR (270MHz, CH₃OH-d₄) δ 8.48 (s, 1H), 8.30 (d, J=1.85 Hz, 1H), 8.05 (dd,J=8.58, 1.98 Hz, 1H), 7.92 (d, J=6.86 Hz, 1H), 7.83 (d, J=8.44 Hz, 1H),7.69 (d, J=6.86 Hz, 1H), 4.4.41-4.34 (m, 2H), 4.24-4.16 (m, 2H),3.76-3.69 (m, 2H), 3.51-3.43 (m, 2H), 2.52-2.42 (m, 2H); MS m/z 442(M+1).

EXAMPLE 85

[0880] 4-(1,4-Diazepan-1-yl)-2-[1-naphthylsulfonyl)thieno[3,2-c]pyridineHydrochloride

[0881] The title compound was obtained from tert-butyl4-[2-(1-naphthyl)sulfonyl]thieno-[3,2-c]pyridin-4-yl)-1,4-diazepane-1-carboxylate(15 mg, 0.029 mmol) following Method O to give 12 mg of the desiredproduct yield 90%, 95% pure. ¹H NMR (270 MHz, CH₃OH-d₄) δ 2.40-2.50 (m,2H), 3.45-3.55 (m, 2H), 3.65-3.75 (m, 2H), 4.06-4.26 (m, 2H), 4.27-4.46(m, 2H), 7.58-7.80 (m, 4H), 7.83-7.86 (m, 1H), 8.06 (d, J=8.1 Hz, 1H),8.20 (d, J=8.1 Hz, 1H), 8.48 (s, 1H), 8.53-8.56 (m, 1H), 8.83-8.86 (m,1). m/z=424.06 (M+H−HCl).

EXAMPLE 86

[0882]4-(1,4-Diazepan-1-yl)-2-[4-tert-butylphenylsulfonyl)thieno[3,2-c]pyridineHydrochloride

[0883] The title compound was obtained from tert-butyl4-[2-(4-tert-butylphenyl)sulfonyl]thieno[3,2-c]pyridin-4-yl)-1,4-diazepane-1-carboxylate(6 mg, 11.3 mmol) following Method O to give 4 mg of the desiredproduct, yield 76%, 88% pure. ¹H NMR (270 MHz, CH₃OH-d₄) δ 1.33 (s, 9H),2.41-2.47 (m, 2H), 3.41-3.49 (m, 2H), 3.65-3.78 (m, 2H), 4.15-4.25 (m,2H), 4.29-4.40 (m, 2H), 7.65-7.70 (m, 3H), 7.90 (d, J=5.4 Hz, 1H),8.00-8.04 (m, 2H), 8.37 (s, 1H). m/z=430.06 (M+H-

EXAMPLE 87

[0884]4-(1,4-Diazepan-1-yl)-2-[3,4-dimethylphenylsulfonyl)thieno[3,2-c]pyridineHydrochloride

[0885] The title compound was obtained from tert-butyl 4-[2-(3,4dimethylphenyl)sulfonyl]thieno[3,2-c]pyridin-4-yl)-1,4-diazepane-1-carboxylate(6 mg, 0.012 mmol) following Method O to give 6 mg of the desiredproduct, yield 88%, 89% pure. ¹H NMR (270 MHz, CH₃OH-d₄) δ 2.34 (s, 6H),2.45-2.55 (m, 2H), 3.42-3.51 (m, 2H), 3.67-3.76 (m, 2H), 4.10-4.20 (m,2H), 3.58-3.70 (m, 2H), 7.39-7.41 (m, 1H), 7.64-7.67 (m, 1H), 7.79-7.84(m, 2H), 7.89-7.91 (m, 1H), 8.36 (s, 1H). m/z=402.07 (M+H−HCl).

EXAMPLE 88

[0886]2-[(4-Bromophenyl)sulfonyl]-4-(1,4-diazepan-1-yl)thieno[3,2-c]pyridineHydrochloride

[0887] Trifluoroacetic acid (1 mL) was added slowly to a solution oftert-butyl4-{2-[(4-bromophenyl)thio]thieno[3,2-c]pyridin-4-yl}-1,4-diazepane-1-carboxylate(26 mg, 0.047 mmol) in CH₂Cl₂ at 0° C. The reaction mixture was allowedto reach room temperature, stirred for 40 min and then concentrated invacuo. The residue was twice re-dissolved in MeOH and concentrated invacuo. The residue was again dissolved in MeOH and an excess of 1M HClin diethyl ether (4 mL) was slowly added to the solution. Removal of thesolvents in vacuo afforded the title compound (21 mg, 91%) as ayellowish solid. ¹H NMR (270 MHz, CH₃OH-d₄) δ 8.41 (s, 1H), 8.06-7.99(m, 2H), 7.92 (d, J=6.86 Hz, 1H), 7.87-7.80 (m, 2H), 7.66 (d, J=6.86 Hz,1H), 4.38-4.31 (m, 2H), 4.22-4.14 (m, 2H), 3.74-3.67 (m, 2H), 3.50-3.42(m, 2H), 2.51-2.39 (m, 2H); MS m/z 452 (M+1).

EXAMPLE 89

[0888] 2-(Phenylsulfonyl)-4-piperazin-1-ylthieno[3,2-c]pyridineHydrochloride

[0889] To a stirred solution of tert-butyl4-[2-(phenylthio)thieno[3,2-c]pyridin-4-yl]piperazine-1-carboxylate (350mg, 0.819 mmol) in ethanol was added oxone in water solution. Thereaction was monitored by LCMS. When all starting material was consumed,the chromatogram showed two major peaks, the product and the N-oxide.After purification by preparative HPLC, the resulting Boc-material wastreated with HCl in ether. The solution was centrifugated and thesupernatant was removed. Ether was added, then centrifugated anddecanted (repeated three times) to remove the excess HCl. The remainingether was finally evaporated in a SpeedVac concentrator. Yield 18%, HPLCpurity=98%, m/z=360.0 (M+H).

[0890]¹H NMR (270 MHz, CH₃OH-d4) δ ppm 3.56 (m, 4H) 4.08 (m, 4H) 7.68(m, 4H) 7.77 (dd, J=6.60, 0.79 Hz, 1H) 8.04 (d, J=6.33 Hz, 1H) 8.12 (m,2H) 8.39 (d, J=0.79 Hz, 1H).

EXAMPLE 90

[0891]2-(3-Methoxy-benzenesulfonyl)-4-piperazin-1-yl-thieno[3,2-c]pyridineHydrochloride

[0892]4-[2-(3-Methoxy-phenylsulfanyl)-thieno[3,2-c]pyridin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester was obtained from 3-methoxythiophenol (130 μl, 1mmol) and tert-Butyl4-(2-bromothieno[3,2-c]pyridin-4-yl)piperazine-1-carboxylate (215 mg,0.52 mmol). 120 mg, 50%) were obtained by the application of the generalMethod M described above. ¹H NMR (270 MHz, CDCl₃) δ 1.48 (s, 9H),3.42-3.51 (m, 4H), 3.58-3.67 (m, 4H), 3.74 (s, 3H), 6.76 (dd, J=8.18,2.38 Hz, 1H), 6.84-6.92 (m, 2H), 7.16-7.23 (m, 2H), 7.51 (s, 1H), 8.04(d, J=5.81 Hz, 1H); MS m/z 458 (M+1). The title compound was thereforeobtained from4-[2-(3-methoxy-phenylsulfanyl)-thieno[3,2-c]pyridin-4-yl]-piperazine-1-carboxylicacid tert-butyl (7 mg, 7%), after triturating with diethyl ether, as abeige solid, by the application of the general procedures B and Cdescribed above. ¹H NMR (270 MHz, CD₃OD) δ 8.31 (s, 1H), 8.09 (d, J=6.33Hz, 1H), 7.71-7.62 (m, 2H), 7.59-7.50 (m, 2H), 7.30-7.23 (m, 1H),3.98-3.92 (m, 4H), 3.87 (s, 3H), 3.54-3.48 (m, 4H); MS m/z 390 (M+1).

EXAMPLE 91

[0893]2-(4-Methoxy-benzenesulfonyl)-4-piperazin-1-yl-thieno[3,2-c]pyridineHydrochloride

[0894]4-[2-(4-Methoxy-phenylsulfanyl)-thieno[3,2-c]pyridin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester was obtained from 4-methoxythiophenol (130 ul, 1mmol) and tert-butyl4-(2-bromothieno[3,2-c]pyridin-4-yl)piperazine-1-carboxylate (215 mg,0.52 mmol). 100 mg, 42% were isolated by the application of the generalMethod M described above. ¹H NMR (270 MHz, CDCl₃) δ 1.48 (s, 9H),3.40-3.47 (m, 4H), 3.58-3.65 (m, 4H), 3.79 (s, 3H), 6.83-6.89 (m, 2H),7.15 (d, J=5.54 Hz, 1H), 7.35 (s, 1H), 7.38-7.43 (m, 2H), 7.99 (d,J=5.81 Hz, 1H); MS m/z 458 (M+1).

[0895]4-[2-(4-methoxy-phenylsulfanyl)-thieno[3,2-c]pyridin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester was obtained (25 mg, 23%) as a clear liquid by theapplication of the general procedure B described above. ¹H NMR (270 MHz,CDCl₃) δ 1.48 (s, 9H), 3.67-3.91 (m, 11H), 7.01 (d, J=8.97 Hz, 2H),7.27-7.37 (m, 1H), 7.93 (d, J=8.97 Hz, 2H), 8.01-8.19 (m, 2H); MS m/z490 (M+1). The title compound was thereby obtained following ProcedureC): ¹H NMR (CD₃OD) δ 8.25 (s, 1H), 8.09-7.89 (m, 3H), 7.69 (d, J=6.33Hz, 1H), 7.17-7.10 (m, 2H), 4.00-3.93 (m, 4H), 3.87 (s, 3H), 3.55-3.48(m, 4H); MS m/z 390 (M+1).

EXAMPLE 92

[0896]4-Piperazin-1-yl-2-{[4-trifluoromethyl)phenyl]sulfonyl}thieno[3,2-c]pyridineHydrochloride

[0897]2-{[4-(Trifluoromethyl)phenyl]thio}-4-piperazin-1-ylthieno[3,2-c]pyridine(0.42 mmol) was dissolved in TFA (1.5 mL) at 0° C., stirred for 15 minand H₂O₂ (100 μL) was added. The mixture was stirred at room temperatureover night. NaOH (2 M) was added, extraction with ethyl acetate (3×),washed with brine, dried over NaSO₄, The solvent was removed and theproduct was purified by preparative HPLC to afford 154.7 mg (86.2%). ¹HNMR (270 MHz, DMSO-d₆) δ ppm 9.79 (s, 1H) 8.56 (s, 1H) 8.35 (d, J=8.44Hz, 2H) 8.12-8.05 (m, 3H) 7.79 (d, J=6.33 Hz, 1H) 3.98-3.96 (m, 4H)3.32-3.31 (m, 4H); LC-MS 428 (M−H)⁺; Purity (HPLC) 95%

EXAMPLE 93

[0898]2-[12-tert-Butylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridineHydrochloride

[0899] The title compound was prepared following Method M-O. Yield: 10.6mg (6.3%) of2-[[2-tert-butylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride. ¹H NMR (270 MHz, DMSO-d₆) δ ppm 9.57 (s, 1H) 8.42 (s, 1H)8.26-8.22 (m, 1H) 8.06-8.04 (m, 1H) 7.68-7.55 (m, 4H) 3.87-3.86 (m, 4H)3.34-3.33 (m, 4H) 1.51-1.43 (m, 9H); LC-MS 400 (M−H)⁺; Purity (HPLC)90%.

EXAMPLE 94

[0900]2-[(3,4-Dichlorophenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamideHydrochloride

[0901] The title compound was prepared following Method M-O. Yield: 47.9mg (22.9%). ¹H NMR (270 MHz, DMSO-d₆) δ ppm 9.36 (s, 1H) 8.51 (s, 1H)8.38 (d, J=2.11 Hz, 1H 8.06-7.94 (m, 3H) 7.70-7.68 (m, 1H) 3.81-3.77 (m,4H) 3.31-3.29 (m, 4H); LC-MS 427 (M−H)⁺; Purity (HPLC) 95%.

EXAMPLE 95

[0902]2-[(4-tert-Butylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridineHydrochloride

[0903] Oxone (0.52 g, 0.84 mmol) in water (4 mL), buffered to pH ˜6 withsodium oxide acetate, was added to2-[(4-tert-butylphenyl)thio]-4-piperazin-1-ylthieno[3,2-c]pyridine (0.42mmol) in ethanol (30 mL). The mixture was stirred in room temperaturefor 2 h and more oxone (0.52 g, 0.84 mmol) was added. The reaction wasstirred over night. Water was added to the mixture, extraction withdichloromethane (2×20 mL) and the solvent was removed. The products werepurified by preparative HPLC. Yield: 41.9 mg (22.0%). ¹H NMR (500 MHz,CH₃OH-d₄) δ ppm 8.38 (s, 1H) 8.05-8.01 (m, 3H) 7.80 (d, J=6.59 Hz, 1H)7.71-7.69 (m, 2H) 4.15-4.13 (m, 4H) 3.59-3.57 (4H) 1.37-1.33 (m, 9H);LC-MS 416 (M−H)⁺; Purity (HPLC) 95%.

EXAMPLE 96

[0904] 2-(1-Naphthylsulfonyl)-4-piperazin-1-ylthieno[3,2-c]pyridineHydrochloride

[0905] The title compound was prepared following Method M-O. Yield: 3.4mg (0.2%). ¹H NMR (270 MHz, DMSO-d₆) δ ppm 9.34 (s, 1H) 8.82 (s, 1H)8.44 (s, 1H) 8.26-8.06 (m, 5H) 7.79-7.65 (m, 3H) 3.79-3.78 (m, 4H)3.32-3.30 (m, 4H); LC-MS 410 (M−H)⁺; Purity (HPLC) 95%.

EXAMPLE 97

[0906]2-[(3-Fluorophenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamideHydrochloride

[0907] 2-Bromo-4-chlorothieno[3,2-c]pyridine (190 mg, 0.50 mmol) in DMF(1 mL) was added to 3-fluorobenzenethiol (95.5 mg, 1.0 mmol), KOH (56mg, 0.2 mmol) and Cu₂O (71 mg, 0.5 mmol) in DMF (1 mL). The reaction washeated to 120° C. over night. The mixture was filtrated through a silicaplug and the solvent was removed. The product was dissolved in TFA (1.5mL) at 0° C. and the solution were stirred for 15 min, H₂O₂ (100 μL) wasadded and the mixture was stirred at room temperature over night. 2MNaOH was added, extraction with etylacetate, washed with brine andsolvent was removed. The product was purified by preparative HPLC.Yield: 30.1 mg (16.1%) ¹H NMR (270 MHz, DMSO-d₆) δ ppm 9.34 (s, 1H) 8.45(s, 1H) 8.16 (d, J=5.69 Hz, 1H) 7.97-7.93 (m, 2H) 7.76-7.62 (m, 3H) 3.30(s, 4H) (4H obscured by solvent signal); LC-MS 378 (M−H)⁺; Purity (HPLC)99%.

EXAMPLE 98

[0908] 2-(Mesitylsulfonyl)-4-piperazin-1-ylthieno[3,2-c]pyridineHydrochloride

[0909] The title compound was prepared following Method M-O. Yield: 32.0mg (16.1%). ¹H NMR (270 MHz, DMSO-d₆) δ ppm 9.32 (s, 1H) 8.20-8.14 (m,2H) 7.66 (d, J=5.69 Hz, 1H) 7.14 (s, 2H) 3.29 (s, 4H) 2.65 (s, 6H) 2.28(s, 3H) (4H obscured by solvent signal); LC-MS 402 (M−H)⁺; Purity (HPLC)95%.

EXAMPLE 99

[0910]2-[(2-Methoxyphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridineHydrochloride

[0911] The title compound was prepared following Method M-O. Yield: 14.7mg (7.6%). ¹H NMR (270 MHz, DMSO-d₆) δ ppm 9.33 (s, 1H) 8.24 (s, 1H)8.15 (d, J=5.94 Hz, 1H) 8.00 (dd, J=7.92, 1.48 Hz, 1H) 7.77-7.68 (m, 2H)7.28-7.18 (m, 2H) 3.30 (s, 4H) (7H obscured by solvent signal); LC-MS390 (M−H)+Purity (HPLC) 99%.

EXAMPLE 100

[0912]2-[(2,4-Dimethoxyphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridineHydrochloride

[0913] The title compound was prepared following Method M-O. Yield: 42.7mg (20.5%). ¹H NMR (270 MHz, DMSO-d₆) δ ppm 9.39 (s, 1H) 8.37 (s, 1H)8.13 (d, J=5.69 Hz, 1H) 7.68-7.66 (m, 2H) 7.54 (d, J=2.23 Hz, 1H) 7.19(d, J=8.66 Hz, 1H) 3.29 (s, 4H) (10H obscured by solvent signal); LC-MS420 (M−H)⁺; Purity (HPLC) 98%.

EXAMPLE 101

[0914]2-[(2,4-Dimethylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridineHydrochloride

[0915] The title compound was prepared following Method M-O. Yield: 17.8mg (9.3%). ¹H NMR (270 MHz, DMSO-d₆) δ ppm 9.32 (s, 1H) 8.27 (s, 1H)8.15 (d, J=5.94 Hz, 1H) 8.00 (d, J=8.17 Hz, 1H) 7.67 (d, J=5.94 Hz, 1H)7.35-7.26 (m, 2H) 3.29 (s, 4H) 2.34 (s, 3H) (7H obscured by solventsignal); LC-MS 388 (M−H)+Purity (HPLC) 98%.

EXAMPLE 102

[0916]2-[(2,5-Dimethylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridineHydrochloride

[0917] The title compound was prepared following Method M-O. Yield: 16.9mg (8.8%). ¹H NMR (270 MHz, DMSO-d₆) δ ppm 9.17 (s, 1H) 8.29 (s, 1H)8.18-18.15 (m, 1H) 7.94 (s, 1H) 7.66 (d, J=5.69 Hz, 1H) 7.47 (d, J=7.67Hz, 1H) 7.32 (d, J=8.16 Hz, 1H) 3.29 (s, 2H) 2.42 (s, 3H) (7H obscuredby solvent signal); LC-MS 388 (M−H)⁺; Purity (HPLC) 99%.

EXAMPLE 103

[0918] 2-[(2-Ethylphenyl)sulfonyl-4-piperazin-1-ylthieno[3,2-c]pyridineHydrochloride

[0919] The title compound was prepared following Method M-O. Yield: 22.6mg (11.2%). ¹H NMR (270 MHz, DMSO-d₆) δ ppm 9.19 (s, 1H) 8.32 (s, 1H)8.17 (d, J=5.69 Hz, 1H) 8.08 (d, J=7.92 Hz, 1H) 7.73-7.66 (m, 2H) 7.52(t, J=7.67 Hz, 2H) 3.29 (s, 4H) 3.00 (q, J=7.34 Hz, 2H) 1.10 (m, 3H) (4Hobscured by solvent signal); LC-MS 388 (M−H)⁺; Purity (HPLC) 100%.

[0920] Intermediate 70

[0921] Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate

[0922] 2-Bromo-4-chlorothieno[3,2-c]pyridine (5.00 g, 20.1 mmol) wassuspended in dry ether (100 ml) and the mixture was cooled to −78° C.under N₂-atmosphere. n-BuLi (1.6M in hexane, 15 mL) was added and thereaction mixture was stirred at −78° C. for 2 h. SO₂ (g) was thenbubbled threw the reaction mixture for 1 h. After the gas bubbling hadstopped the reaction mixture was stirred fore one more hour at −78° C.and was then allowed to warm to room temperature. The precipitate thathad formed was filtered and washed with ether to give the sulfonatelithium salt (3.59 g, 74%) that was used in the next step withoutfurther purification.

[0923]¹H NMR (270 MHz, DMSO-d₆) δ ppm 7.26 (s, 1H) 7.99 (d, J=5.54 Hz,1H) 8.14 (d, J=5.54 Hz, 1H). MS (M−Li+1) 234.

[0924] Benzylation of Sulfinate Salts (Method P)

[0925] To a suspension of lithium4-chlorothieno[3,2-c]pyridine-2-sulfinate (100 mg, 0.42 mmol) in dry DMF(2 mL) was added a benzylbromide (0.83 mmol, 2 equiv.) and the mixtureheated with stirring for 16 h at 110° C. Analysis by LCMS showed desiredproduct and no starting material remaining. The mixture was treated withpolystyrene-thiophenol (200 mg) and was rolled for 16 h. The suspensionwas filtered washing with further DMF (2 mL). This material was reactedfurther without purification.

[0926] Nucleophilic Substitution of Chlorine (Method Q)

[0927] To a crude solutions of benzylsulfone in DMF (4 mL) are addedpotassium carbonate (172 mg, 1.25 mmol) andtert-butyl-piperazine-1-carboxylate (155 mg, 0.84 mmol). The resultingmixtures are heated for 16 h at 110° C. LCMS shows desired compound andno starting material. The reaction mixtures are filtered and then thesolvent removed under reduced pressure. The desired compounds areisolated pure following preparative HPLC.

[0928] BOC-Deprotection (Method R)

[0929] The BOC N-protected piperazine derivatives are dissolved inHCl/diethyl ether (1 mL, 1.0M) at room temperature and stirred for 16 h.Removal of the solvent under reduced pressure gave the crudehydrochloride salts. Trituration with acetonitrile gives the desiredcompound as a white solid.

[0930] Intermediate 71

[0931]tert-Butyl-4-[2-(benzylsulfonyl)thieno[3,2-c]pyridin-4-yl]piperazine-1-carboxylate

[0932] Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) wastreated with benzylbromide (0.59 mmol) as described in Method P aboveand then reacted further with tert-butyl-piperazine-1-carboxylate asdescribed in Method Q. Yield 0.009 g (7% over two steps).

[0933]¹H NMR (300 MHz, CDCl₃) δ 8.14 (d, J=5.5 Hz 1H), 7.27-7.40 (m,5H), 7.15-7.21 (m, 2H), 4.45 (s, 2H), 3.50-3.56 (m, 4H), 3.40-3.45 (m,4H), 1.49 (s, 9H); MS (ESI+) for C23H27N3O4S₂ m/z 474 (M+H)⁺. HPLC 77%,R_(T) 3.93 min (ACE3 C8 50×4 mm, 5-50% acetonitrile in 3 min).

[0934] Intermediate 72

[0935]tert-Butyl-4-(2-{[4-(trifluoromethyl)benzyl]sulfonyl}thieno[3,2-c]pyridin-4-yl)piperazine-1-carboxylate

[0936] Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) wastreated with 4-(trifluoromethyl)benzylbromide (0.59 mmol) as describedin Method P above and then reacted further withtert-butyl-piperazine-1-carboxylate as described in Method QF. Yield0.02 g (16% over two steps). Beige solid. ¹H NMR (300 MHz, CDCl₃) δ 8.16(d, J=6 Hz1 H), 7.53-7.61 (d, J=9 Hz 2H), 7.49 (s, 1H), 7.26-7.36 (m,4H), 4.51 (s, 2H), 3.49-3.60 (m, 4H), 3.36-3.49 (m, 4H), 1.49 (s, 9H);MS (ESI+) for C24H26F3N3O4S₂ m/z 542 (M+H)⁺. HPLC 71%, R_(T) 4.07 min(ACE3 C8 50×4 mm, 5-50% acetonitrile in 3 min).

[0937] Intermediate 73

[0938]tert-Butyl-4-{2-[(3-bromobenzyl)sulfonyl]thieno[3,2-c]pyridin-4-yl}piperazine-1-carboxylate

[0939] Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) wastreated with 3-bromobenzylbromide (0.59 mmol) as described in Method Pabove and then reacted further with tert-butyl-piperazine-1-carboxylateas described in Method Q. Yield 0.023 g (10% over two steps). Beigesolid. ¹H NMR (300 MHz, CDCl₃) δ 8.16 (d, J=6 Hz, 1H), 7.50-7.55 (m,2H), 7.32-7.40 (m, 2H), 7.10-7.24 (m, 3H), 4.44 (s, 2H), 3.61-3.73 (m,8H), 1.50 (s, 9H); MS (ESI+) for C23H26BrN3O4S₂ m/z 554 (M+H)⁺. HPLC77%, R_(T) 4.07 min (ACE3 C8 50×4.6 mm, 5-50% acetonitrile in 3 min).

[0940] Intermediate 74

[0941]tert-Butyl-4-(2-{[3-(trifluoromethyl)benzyl]sulfonyl}thieno[3,2-c]pyridin-4-yl)piperazine-1-carboxylate

[0942] Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) wastreated with 3-(trifluoromethyl)benzylbromide (0.59 mmol) as describedin Method P above and then reacted further withtert-butyl-piperazine-1-carboxylate as described in Method Q. Yield0.023 g (10% over two steps). Beige solid. ¹H NMR (300 MHz, CDCl₃) δ8.14 (d, J=6 Hz, 1H), 7.85-7.91 (m, 1H), 7.61-7.72 (m, 2H), 7.50-7.60(m, 1H), 7.12-7.31 (m, 2H), 4.74 (s, 2H), 3.52-3.71 (m, 8H), 1.50 (s,9H); MS (ESI+) for C24H26F3N3O4S₂ m/z 542 (M+H)⁺. HPLC 85%, R_(T) 2.13min (YMC ODS AQ, 33×3 mm, 10-90% acetonitrile in 3 min).

[0943] Intermediate 75

[0944]tert-Butyl-4-(2-{[2,5-bis(trifluoromethyl)benzyl]sulfonyl}thieno[3,2-c]pyridin-4-yl)piperazine-1-carboxylate

[0945] Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) wastreated with 2,5-bis(trifluoromethyl)benzylbromide (0.59 mmol) asdescribed in Method P above and then reacted further withtert-butyl-piperazine-1-carboxylate as described in Method Q. Yield 0.01g (4% over two steps). Beige solid. ¹H NMR (300 MHz, CDCl₃) δ 8.16 (d,J=5.8 Hz1 H), 8.00 (s, 1H), 7.74-7.85 (m, 3H), 4.76 (s, 2H), 3.56-3.64(m, 4H), 3.47-3.56 (m, 4H), 1.49 (s, 9H); MS (ESI+) for C25H25F6N3O4S₂m/z 610 (M+H)⁺. HPLC 73%, R_(T) 2.36 min (YMC ODS AQ, 33×3 mm, 10-90%acetonitrile in 3 min).

[0946] Intermediate 76

[0947] tert-Butyl4-{2-[(4-methylbenzyl)sulfonyl]thieno[3,2-c]pyridin-4-yl}piperazine-1-carboxylate

[0948] Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) wastreated with 4-methylbenzylbromide (0.59 mmol) as described in Method Pabove and then reacted further with tert-butyl-piperazine-1-carboxylateas described in Method Q. Yield 0.005 g (3% over two steps). Beigesolid. ¹H NMR (300 MHz, CDCl₃) δ 8.15 (d, J=6 Hz 1H), 7.40 (s, 1H),7.00-7.16 (m, 4H), 4.42 (s, 2H), 3.46-3.60 (m, 4H), 3.37-3.46 (m, 4H),2.34 (s, 3H), 1.49 (s, 9H); MS (ESI+) for C24H29N3O4S₂ m/z 488 (M+H)⁺.HPLC 69%, R_(T) 2.06 min (YMC ODS AQ, 33×3 mm, 10-90% acetonitrile in 3min).

[0949] Intermediate 77

[0950] tert-Butyl4-(2-{[5-chloro-2-(trifluoromethyl)benzyl]sulfonyl}thieno[3,2-c]pyridin-4-yl)piperazine-1-carboxylate

[0951] Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) wastreated with 5-chloro-2-(trifluoromethyl)benzylbromide (0.59 mmol) asdescribed in Method P above and then reacted further withtert-butyl-piperazine-1-carboxylate as described in Method Q. Yield0.019 g (7.5% over two steps). Beige solid. ¹H NMR (300 MHz, CDCl₃) δ8.12-8.14 (m, 1H), 7.80-7.88 (m, 2H), 7.47-7.66 (m, 2H), 4.71 (s, 2H),3.74-3.83 (m, 4H), 3.63-3.72 (m, 4H), 1.49 (s, 9H); MS (ESI+) forC24H25ClF3N3O4S₂ m/z 576 (M+H)⁺. HPLC 74%, R_(T) 2.30 min (YMC ODS AQ,33×3 mm, 10-90% acetonitrile in 3 min).

[0952] Intermediate 78

[0953] tert-Butyl4-{2-[(3,4-difluorobenzyl)sulfonyl]thieno[3,2-c]pyridin-4-yl}piperazine-1-carboxylate

[0954] Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) wastreated with 3,4-bis(trifluoromethyl)benzylbromide (0.59 mmol) asdescribed in Method P above and then reacted further withtert-butyl-piperazine-1-carboxylate as described in Method Q. Yield0.014 g (6% over two steps). Beige solid. ¹H NMR (300 MHz, CDCl₃) δ8.17-8.21 (m, 1H), 7.71 (s, 1H), 7.07-7.39 (m, 4H), 4.59 (s, 2H),3.55-3.68 (m, 8H), 1.49 (s, 9H); MS (ESI+) for C23H25F2N3O4S₂ m/z 510(M+H)⁺. HPLC 64%, R_(T) 2.02 min (YMC ODS AQ, 33×3 mm, 10-90%acetonitrile in 3 min).

[0955] Intermediate 79

[0956] tert-Butyl4-{2-[(3,5-dimethoxybenzyl)sulfonyl]thieno[3,2-c]pyridin-4-yl}piperazine-1-carboxylate

[0957] Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) wastreated with 3,5-dimethoxybenzylbromide (0.59 mmol) as described inMethod P above and then reacted further withtert-butyl-piperazine-1-carboxylate as described in Method Q. Yield 0.02g (10% over two steps). Beige solid. ¹H NMR (300 MHz, CDCl₃) δ 8.14-8.18(m, 1H), 7.55 (s, 1H), 6.40-6.45 (m, 1H), 6.26-6.34 (m, 2H), 4.39 (s,2H), 3.54-3.72 (m, 14H), 1.50 (s, 9H); MS (ESI+) for C25H31N3O6S₂ m/z534 (M+H)⁺. HPLC 69%, R_(T) 1.99 min (YMC ODS AQ, 33×3 mm, 10-90%acetonitrile in 3 min).

EXAMPLE 104

[0958] 4-(Piperazinyl)-2-(3-methoxybenzyl-sulfonyl)-thienopyridine

[0959] A 1:1 mixture of lithium 4-chloro-thienopyridine-2-sulfinate(0.176 g, 0.734 mmol) and 2-methoxybenzylbromide (0.295 g, 1.47 mmol) inDMF (5 mL) was heated at 100° C. for 2 h. To the mixture was addedBoc-piperazine (546 mg, 2.94 mmol) and the reaction was heated at 110°C. for 1.5 h. The solvent was removed and the crude product was purifiedby preparative HPLC to obtain 17.4 mg of4-(4-t-butyl-oxy-carbonyl-piperazinyl)-2-(3-methoxybenzylsulfonyl)-thienopyridine.The boc-protected product was dissolved in 2 mL of MeOH and 4 mL ofHCl/ether was added to obtain 21.9 mg of4-(piperazinyl)-2-(3-methoxybenzylsulfonyl)-thienopyridine. ¹HNMR(CD₃OD/D₂O 1:1) δ 6.42-6.38 (m, 1H), 7.51-7.48 (m, 1H), 7.39-7.35 (m,1H), 6.92-6.85 (m, 1H), 6.64-6.59 (m, 1H), 6.48-6.39 (m, 2H), 3.64-3.58(m, 4H), 3.19-3.13 (m, 4H), 2.96 (s, 3H), 2.92 (s, 2H); MS (ESI) 404(M+H)⁺; Purity (HPLC, column YMC) 94%.

[0960] Intermediate 80

[0961]tert-Butyl-4-[2-(benzylsulfonyl)thieno[3,2-c]pyridin-4-yl]piperazine-1-carboxylate

[0962] Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) wastreated with benzylbromide (0.59 mmol) as described in Method P aboveand then reacted further with tert-butyl-piperazine-1-carboxylate asdescribed in Method Q. Yield 0.00 g (7% over two steps). Beige solid. ¹HNMR (300 MHz, CDCl₃) δ 8.14 (d, J=5.5 Hz 1H), 7.27-7.40 (m, 5H),7.15-7.21 (m, 2H), 4.45 (s, 2H), 3.50-3.56 (m, 4H), 3.40-3.45 (m, 4H),1.49 (s, 9H); MS (ESI+) for C23H27N3O4S₂ m/z 474 (M+H)⁺. HPLC 77%, R_(T)3.93 min (ACE3 C8 50×4 mm, 5-50% acetonitrile in 3 min).

EXAMPLE 105

[0963] 2-(Benzylsulfonyl)-4-piperazin-1-ylthieno[3,2-c]pyridineHydrochloride

[0964] tert-Butyl4-[2-(benzylsulfonyl)thieno[3,2-c]pyridin-4-yl]piperazine-1-carboxylate(0.01 g, 0.02 mmol) was treated as described in Method R to give thedesired product as a white solid. Yield 0.009 g, (100%). White solid. ¹HNMR (300 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.13-8.20 (d, J=8 Hz1 H), 8.00(s, 1H), 7.64-7.71 (m, 1H), 7.18-7.35 (m, 5H), 4.93 (s, 2H), 3.60-3.70(m, 4H), 3.22.3.34 (m, 4H); MS (ESI+) for C18H19N3O2S2. C1 H m/z 374(M+H)⁺. HPLC 90%, R_(T) 2.91 min (ACE3 C8 50×4.6 mm, 5-50% acetonitrilein 3 min).

[0965] Intermediate 81

[0966]tert-Butyl-4-(2-{[4-(trifluoromethyl)benzyl]sulfonyl}thieno[3,2-c]pyridin-4-yl)piperazine-1-carboxylate

[0967] Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) wastreated with 4-(trifluoromethyl)benzylbromide (0.59 mmol) as describedin Method P above and then reacted further withtert-butyl-piperazine-1-carboxylate as described in Method Q. Yield 0.02g (16% over two steps). Beige solid. ¹H NMR (300 MHz, CDCl₃) δ 8.16 (d,J=6 Hz1 H), 7.53-7.61 (d, J=9 Hz 2H), 7.49 (s, 1H), 7.26-7.36 (m, 4H),4.51 (s, 2H), 3.49-3.60 (m, 4H), 3.36-3.49 (m, 4H), 1.49 (s, 9H); MS(ESI+) for C24H26F3N3O4S₂ m/z 542 (M+H)⁺. HPLC 71%, R_(T) 4.07 min (ACE3C8 50×4 mm, 5-50% acetonitrile in 3 min).

EXAMPLE 106

[0968]4-Piperazin-1-yl-2-{[4-(trifluoromethyl)benzyl]sulfonyl}thieno[3,2-c]pyridineHydrochloride

[0969] tert-Butyl4-(2-{[4-(trifluoromethyl)benzyl]sulfonyl}thieno[3,2-c]pyridin-4-yl)piperazine-1-carboxylate(0.02 g, 0.03 mmol) was treated as described in Method R to give thedesired product as a white solid. Yield 0.014 g (100%) White solid. ¹HNMR (300 MHz, DMSO-d6) δ 9.25 (s, 1H), 8.12-8.22 (m, 2H), 7.66-7.77 (m,4H), 7.41-7.52 (m, 2H), 5.12 (s, 2H), 3.22-3.35 (m, 4H); MS (ESI+) forC19H18F3N3O2S2. C1 H m/z 442 (M+H)⁺. HPLC 90%, R_(T) 3.53 min (ACE3 C850×4.6 mm, 5-50% acetonitrile in 3 min).

[0970] Intermediate 82

[0971]tert-Butyl-4-{2-[(3-bromobenzyl)sulfonyl]thieno[3,2-c]pyridin-4-yl}piperazine-1-carboxylate

[0972] Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) wastreated with 3-bromobenzylbromide (0.59 mmol) as described in Method Pabove and then reacted further with tert-butyl-piperazine-1-carboxylateas described in Method Q. Yield 0.023 g (10% over two steps). Beigesolid. ¹H NMR (300 MHz, CDCl₃) δ 8.16 (d, J=6 Hz, 1H), 7.50-7.55 (m,2H), 7.32-7.40 (m, 2H), 7.10-7.24 (m, 3H), 4.44 (s, 2H), 3.61-3.73 (m,8H), 1.50 (s, 9H); MS (ESI+) for C23H26BrN3O4S₂ m/z 554 (M+H)⁺. HPLC77%, R_(T) 4.07 min (ACE3 C8 50×4.6 mm, 5-50% acetonitrile in 3 min).

EXAMPLE 107

[0973] 2-[(3-Bromobenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridineHydrochloride

[0974] tert-Butyl4-{2-[(3-bromobenzyl)sulfonyl]thieno[3,2-c]pyridin-4-yl}piperazine-1-carboxylate(0.023 g, 0.04 mmol) was treated as described in Method R to give thedesired product as a white solid. Yield 0.013 g (67%) White solid. ¹HNMR (300 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.18 (d, J=6 Hz, 1H), 8.05 (s,1H), 7.70 (d, J=6 Hz, 1H), 7.53-7.58 (m, 1H), 7.43-7.45 (m, 1H),7.19-7.32 (m, 2H), 4.98 (s, 2H), 3.24-3.35 (m, 4H); MS (ESI+) forC18H18BrN3O2S2. C1 H m/z 452 (M+H)⁺. HPLC 90%, R_(T) 3.30 min (ACE3 C850×4.6 mm, 5-50% acetonitrile in 3 min).

[0975] Intermediate 83

[0976] tert-Butyl4-{2-[(3,4-difluorobenzyl)sulfonyl]thieno[3,2-c]pyridin-4-yl}piperazine-1-carboxylate

[0977] Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) wastreated with 3,4-bis(trifluoromethyl)benzylbromide (0.59 mmol) asdescribed in Method P above and then reacted further withtert-butyl-piperazine-1-carboxylate as described in Method Q. Yield0.014 g (6% over two steps). Beige solid. ¹H NMR (300 MHz, CDCl₃) δ8.17-8.21 (m, 1H), 7.71 (s, 1H), 7.07-7.39 (m, 4H), 4.59 (s, 2H),3.55-3.68 (m, 8H), 1.49 (s, 9H); MS (ESI+) for C23H25F2N3O4S₂ m/z 510(M+H)⁺. HPLC 64%, R_(T) 2.02 min (YMC ODS AQ, 33×3 mm, 10-90%acetonitrile in 3 min).

EXAMPLE 108

[0978]2-[(2,3-Difluorobenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridineHydrochloride

[0979] The BOC group was removed from tert-butyl4-{2-[(3,4-difluorobenzyl)sulfonyl]thieno[3,2-c]pyridin-4-yl}piperazine-1-carboxylateusing Method R. Yield 0.068 g (100%). White solid.

[0980]¹H NMR (300 MHz, DMSO-d₆) δ 9.34 (s, 1H), 8.22 (s, 1H), 8.18 (d,J=5.5 Hz, 1H), 7.70 (d, J=5.5 Hz, 1H), 7.26-7.35 (m, 1H), 7.15-7.22 (m,1H), 7.05-7.14 (m, 1H), 5.08 (s, 2H), 3.34-3.42 (m, 4H), 3.25-3.34 (m,4H); MS (ESI+) for C18H17F2 N3O2S2. C1 H m/z 410 (M+H)⁺. HPLC 90%, R_(T)1.07 min (YMC ODS AQ, 33×3 mm, 20-50% acetonitrile in 1.5 min).

EXAMPLE 109

[0981] 2-[(4-Bromobenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridineHydrochloride

[0982] Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.42 mmol) wastreated with 4-bromobenzylbromide (0.59 mmol) as described in Method Pabove and then reacted further with tert-butyl-piperazine-1-carboxylateas described in Method Q. The BOC protecting group was removed usingMethod R. Yield 0.024 g (12% over three steps). White solid. ¹H NMR (300MHz, DMSO-d6) δ 8.99 (s, 1H), 8.18 (d, J=5.5 Hz, 1H), 8.02 (s, 1H), 7.69(d, J=5.5 Hz, 1H), 7.53 (d, J=8.5 Hz, 2H), 7.17 (d, J=8.5 Hz, 2H), 4.95(s, 2H), 3.62-3.68 (m, 4H), 3.27-3.32 (m, 4H); MS (ESI+) forC18H18BrN3O2S2. C1 H m/z 454 (M+H)⁺. HPLC 90%, R_(T) 1.24 min (YMC ODSAQ, 33×3 mm, 20-50% acetonitrile in 1.5 min).

[0983] Intermediate 84

[0984]tert-Butyl-4-(2-{[2,5-bis(trifluoromethyl)benzyl]sulfonyl}thieno[3,2-c]pyridin-4-yl)piperazine-1-carboxylate

[0985] Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) wastreated with 2,5-bis(trifluoromethyl)benzylbromide (0.59 mmol) asdescribed in Method P above and then reacted further withtert-butyl-piperazine-1-carboxylate as described in Method Q. Yield 0.01g (4% over two steps). Beige solid. ¹H NMR (300 MHz, CDCl₃) δ 8.16 (d,J=5.8 Hz1 H), 8.00 (s, 1H), 7.74-7.85 (m, 3H), 4.76 (s, 2H), 3.56-3.64(m, 4H), 3.47-3.56 (m, 4H), 1.49 (s, 9H); MS (ESI+) for C25H25F6 N3O4S₂m/z 610 (M+H)⁺. HPLC 73%, R_(T) 2.36 min (YMC ODS AQ, 33×3 mm, 10-90%acetonitrile in 3 min).

EXAMPLE 110

[0986]2-{[2,5-Bis(trifluoromethyl)benzyl]sulfonyl}-4-piperazin-1-ylthieno[3,2-c]pyridineHydrochloride

[0987] The BOC group was removed from tert-butyl4-(2-{[2,5-(trifluoromethyl)benzyl]sulfonyl}thieno[3,2-c]pyridin-4-yl)piperazine-1-carboxylateusing Method R. Yield 0.024 g (100%). White solid. ¹H NMR (300 MHz,DMSO-d₆) δ 9.30 (s, 1H), 8.25 (s, 1H), 8.19 (d, J=5.5 Hz, 1H), 8.00-8.07(m, 2H), 7.85 (s, 1H), 7.69 (d, J=5.5 Hz, 1H), 5.22 (s, 2H), 3.24-3.33(m, 4H); MS (EST+) for C20H17F6N3O2S2. C1 H m/z 510 (M+H)⁺. HPLC 90%,R_(T) 1.08 min (YMC ODS AQ, 33×3 mm, 30-60% acetonitrile in 1.5 min).

[0988] Intermediate 85

[0989] tert-Butyl4-{2-[(4-methylbenzyl)sulfonyl]thieno[3,2-c]pyridin-4-yl}piperazine-1-carboxylate

[0990] Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) wastreated with 4-methylbenzylbromide (0.59 mmol) as described in Method Pabove and then reacted further with tert-butyl-piperazine-1-carboxylateas described in Method Q. Yield 0.005 g (3% over two steps). Beigesolid. ¹H NMR (300 MHz, CDCl₃) δ 8.15 (d, J=6 Hz 1H), 7.40 (s, 1H),7.00-7.16 (m, 4H), 4.42 (s, 2H), 3.46-3.60 (m, 4H), 3.37-3.46 (m, 4H),2.34 (s, 3H), 1.49 (s, 9H); MS (ESI+) for C24H29N3O4S₂ m/z 488 (M+H)⁺.HPLC 69%, R_(T) 2.06 min (YMC ODS AQ, 33×3 mm, 10-90% acetonitrile in 3min).

EXAMPLE 111

[0991]2-[(4-Methylbenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridineHydrochloride

[0992] The BOC group was removed from tert-butyl4-{2-[(4-methylbenzyl)sulfonyl]thieno[3,2-c]pyridin-4-yl}piperazine-1-carboxylateusing Method R. Yield 0.05 g (75%). White solid. ¹H NMR (300 MHz,DMSO-d6) δ 9.18 (s, 1H), 8.17 (d, J=5.5 Hz, 1H), 8.01 (s, 1H), 7.67 (d,J=5.5 Hz, 1H), 7.38 (s, 1H), 7.19 (s, 1H), 7.11 (s, 1H), 7.00 (s, 1H),4.86 (s, 2H); MS (ESI+) for C19H21N3O2S2. C1 H m/z 388 (M+H)⁺. HPLC 90%,R_(T) 1.65 min (ACE3 C8 50×3.0 mm, 10-97% acetonitrile in 3 min).

[0993] Intermediate 86

[0994] tert-Butyl4-(2-{[5-chloro-2-(trifluoromethyl)benzyl]sulfonyl}thieno[3,2-c]pyridin-4-yl)piperazine-1-carboxylate

[0995] Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) wastreated with 5-chloro-2-(trifluoromethyl)benzylbromide (0.59 mmol) asdescribed in Method P above and then reacted further withtert-butyl-piperazine-1-carboxylate as described in Method Q. Yield0.019 g (7.5% over two steps). Beige solid. ¹H NMR (300 MHz, CDCl₃) δ8.12-8.14 (m, 1H), 7.80-7.88 (m, 2H), 7.47-7.66 (m, 2H), 4.71 (s, 2H),3.74-3.83 (m, 4H), 3.63-3.72 (m, 4H), 1.49 (s, 9H); MS (ESI+) forC24H25ClF3 N3O4S₂ m/z 576 (M+H)⁺. HPLC 74%, R_(T) 2.30 min (YMC ODS AQ,33×3 mm, 10-90% acetonitrile in 3 min).

EXAMPLE 112

[0996]2-{[5-Chloro-2-(trifluoromethyl)benzyl]sulfonyl}-4-piperazin-1-ylthieno[3,2-c]pyridineHydrochloride

[0997] The BOC group was removed from tert-butyl4-(2-{[5-chloro-2-(trifluoromethyl)benzyl]sulfonyl}thieno[3,2-c]pyridin-4-yl)piperazine-1-carboxylateusing Method r. Yield 0.012 g (92%). White solid. ¹H NMR (300 MHz,DMSO-d₆) δ 9.05 (s, 1H), 8.18-8.23 (m, 2H), 7.78-7.83 (m, 1H), 7.72-7.76(m, 1H), 7.69 (d, J=5.5 Hz, 1H), 7.62-7.65 (m, 1H), 5.07 (s, 2H),3.65-3.72 (m, 4H), 7.25-7.34 (m, 4H); MS (ESI+) for C19H17ClF3N3O2S2. C1H m/z 476 (M+H)⁺. HPLC 90%, R_(T) 1.65 min (ACE3 C8 50×3.0 mm, 10-97%acetonitrile in 3 min).

[0998] Intermediate 87

[0999] tert-Butyl4-{2-[(3,5-dimethoxybenzyl)sulfonyl]thieno[3,2-c]pyridin-4-yl}piperazine-1-carboxylate

[1000] Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) wastreated with 3,5-dimethoxybenzylbromide (0.59 mmol) as described inMethod P above and then reacted further withtert-butyl-piperazine-1-carboxylate as described in Method Q. Yield 0.02g (10% over two steps). Beige solid. ¹H NMR (300 MHz, CDCl₃) δ 8.14-8.18(m, 1H), 7.55 (s, 1H), 6.40-6.45 (m, 1H), 6.26-6.34 (m, 2H), 4.39 (s,2H), 3.54-3.72 (m, 14H), 1.50 (s, 9H); MS (ESI+) for C25H31N3O6S₂ m/z534 (M+H)⁺. HPLC 69%, R_(T) 1.99 min (YMC ODS AQ, 33×3 mm, 10-90%acetonitrile in 3 min).

EXAMPLE 113

[1001]2-[(3,5-Dimethoxybenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridineHydrochloride

[1002] The BOC group was removed from tert-butyl4-{2-[(3,5-dimethoxybenzyl)sulfonyl]thieno[3,2-c]pyridin-4-yl}piperazine-1-carboxylateusing Method R. Yield 0.01 g (62%). White solid. ¹H NMR (300 MHz,DMSO-d₆) δ 9.09 (s, 1H), 8.18 (d, J=6.7 Hz, 1H), 8.02 (s, 1H), 7.69 (d,J=6.7 Hz, 1H), 6.45-6.48 (m, 1H), 6.35-6.38 (m, 2H), 4.84 (s, 2H),3.61-3.67 (m, 4H), 3.58 (s, 6H), 3.24-3.33 (m, 4H). MS (ESI+) forC₂₀H₂₂N₃O₄S₂ m/z 434 (M+H)⁺. HPLC 90%, R_(T) 1.60 min (ACE3 C8 50×3.0mm, 10-97% acetonitrile in 3 min).

EXAMPLE 114

[1003]2-[(2-Naphthylmethyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridineHydrochloride

[1004] 2-(Bromomethyl)naphthalene was used according to Method P-R togive 12.4 mg of the desired product. ¹H NMR (270 MHz, CH₃OH-d₄) δ ppm(obscured by CH₃OH, 4H) 3.70-3.79 (m, 4H) 4.95 (s, 2H) 7.36-7.58 (m, 3H)7.70-7.91 (m, 6H) 8.02 (d, J=6.60 Hz, 1H). MS (M+1) 424.

EXAMPLE 115

[1005]4-Piperazin-1-yl-2-{[4-(1,2,3-thiadiazol-4-yl)benzyl]sulfonyl}thieno[3,2-c]pyridineHydrochloride

[1006] 4-[4-(Bromomethyl)phenyl]-1,2,3-thiadiazole was used according toMethod P-R to give 4.8 mg of the desired product. ¹H NMR (270 MHz,CH₃OH-d₄) δ ppm 3.41-3.50 (m, 4H) 3.54 (s, 2H) 3.89-3.98 (m, 4H) 7.45(d, J=8.44 Hz, 2H) 7.75 (d, J=6.33 Hz, 1H) 7.96-8.13 (m, 4H) 9.31 (s,1H). MS (M+1) 458.

EXAMPLE 116

[1007]1-(4-Pyrrolidin-1-ylphenyl)-2-[(4-piperazine-1-ylthieno[3,2-c]pyridin-2-yl)sulfonyl]ethanoneHydrochloride

[1008] 2-Bromo-1-(4-pyrrolidin-1-ylphenyl)ethanone was used according toMethod P-R to give 19.6 mg of the desired product. ¹H NMR (270 MHz,CH₃OH-d₄) δ ppm 2.02-2.12 (m, 4H) 2.69 (s, 1H) 3.37 (t, J=6.73 Hz, 4H)3.54 (s, 1H) 3.56.3.64 (m, 4H) 4.12-4.22 (m, 4H) 6.55 (d, J=8.97 Hz, 2H)7.78-7.90 (m, 3H) 8.03 (d, J=6.86 Hz, 1H) 8.41 (s, 1H). MS (M+1) 471.

EXAMPLE 117

[1009]1-[4-(Diethylamino)phenyl]-2-[(4-piperazine-1-ylthieno[3,2-c]pyridin-2-yl)sulfonyl]ethanoneHydrochloride

[1010] 2-Bromo-1-[4-(diethylamino)phenyl]ethanone ethanone was usedaccording to Method P-R to give 9.0 mg of the desired product. ¹H NMR(500 MHz, CH₃OH-d₄) δ ppm 1.16 (t, J=7.06 Hz, 6H) 3.49-3.66 (m, 10H)4.14-4.27 (m, 4H) 7.13 (br.s, 2H) 7.85 (d, J=6.59 Hz, 1H) 7.98 (d,J=8.48 Hz, 2H) 8.03 (d, J=6.59 Hz, 1H) 8.47 (s, 1H). MS (M+1) 473.

EXAMPLE 118

[1011]1-(4-Bromophenyl)-2-[(4-piperazin-1-ylthieno[3,2-c]pyridin-2-yl)sulfonyl]ethanone-2

[1012] Bromo-1-(4-bromophenyl)ethanone was used according to method A togive 3.4 mg of the desired product. ¹H NMR (270 MHz, CH₃OH-d₄) δ ppm3.55 (s, 2H) 3.56-3.67 (m, 4H) 4.08-4.26 (m, 4H) 7.68 (d, J=8.44 Hz, 2H)7.79-7.98 (m, 3H) 8.06 (d, J=6.60 Hz, 1H) 8.45 (s, 1H). MS (M+1) 481.

EXAMPLE 119

[1013]1-(3-Methoxyphenyl)-2-[(4-piperazin-1-ylthieno[3,2-c]pyridin-2-yl)sulfonyl]ethanone

[1014] 2-bromo-1-(3-methoxyphenyl)ethanone was used according to methodA to give 1.0 mg of the desired product. ¹H NMR (270 MHz, CH₃OH-d₄) δppm 3.54 (s, 2H) 3.55-6.62 (m, J=10.03 Hz, 4H) 3.82 (s, 3H) 4.06-4.18(m, 4H) 7.20 (dd, J=8.05, 2.24 Hz, 1H) 7.34-7.49 (m, 2H) 7.57 (d, J=7.39Hz, 1H) 7.84 (d, J=6.60 Hz, 1H) 8.06 (d, J=6.60 Hz, 1H) 8.41 (s, 1H). MS(M+1) 432.

EXAMPLE 120

[1015]1-Phenyl-2-[(4-piperazin-1-ylthieno[3,2-c]pyridin-2-yl)sulfonyl]ethanone

[1016] 2-Bromo-1-phenylethanone was used according to method A to give1.2 mg of the desired product. ¹H NMR (270 MHz, CH₃OH-d₄) δ ppm 3.55 (s,2H) 3.57-3.66 (m, 4H) 4.10-4.24 (m, 4H) 7.46-4.57 (m, 2H) 7.66 (t,J=7.39 Hz, 1H) 7.86 (d, J=6.60 Hz, 1H) 8.02 (dd, J=14.12, 6.99 Hz, 3H)8.46 (s, 1H). MS (M+1) 402. TABLE 6

EXAMPLE R¹ R⁴ 121 4-Piperazin-1-yl-1-(toluene-4-sulfonyl)-1H-pyrrolo[3,2-c]pyridine hydrochloride

122 1-(3-Chloro-2-methyl-benzenesulfonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2- c]pyridine hydrochloride

123 1-(3,4-Dimethoxy-benzenesulfonyl)-4-piperidine-1-yl-1H-pyrrolo[3,2-c]- pyridine hydrochloride

124 4-(4-Piperazin-1-yl-pyrrolo[3,2-c]-pyridine-1-sulfonyl)-benzonitrile hydrochloride

125 1-(4,5-Dichloro-thiophene-2-sulfonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridine hydrochloride

126 1-(2-Chloro-4-fluoro-benzenesulfonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2- c]pyridine hydrochloride

127 1-Phenylmethanesulfonyl-4-piperazin-1-yl-1H- pyrrolo [3,2-c]pyridinehydrochloride

128 1-(5-Chloro-thiophene-2-sulfonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]- pyridine hydrochloride

129 1-(4-Butyl-benzenesulfonyl)-4-piperazin-1-yl-1H-pyrrolo(3,2-c)pyridine hydrochloride

130 1-(4-Phenoxy-benzenesulfonyl)-4-piperazin-1-yl-1H-pyrrolo(3,2-c)pyridine hydrochloride

131 1-(Phenylsulfonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2- c]pyridinehydrochloride

132 1-[(4-Chlorophenyl)sulfonyl]-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridine hydrochloride

133 1-[(4-Methoxyphenyl)sulfonyl]-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridine hydrochloride

134 1-[(2-Methoxy-5-methylphenyl)sulfonyl]-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridine hydrochloride

135 4-Piperazin-1-yl-1-{[2-(trifluoromethyl)phenyl]-sulfonyl}-1H-pyrrolo[3,2-c]pyridine hydrochloride

[1017]

[1018] Intermediate 88

[1019] (2E)-3-(1-Benzyl-1H-pyrrol-2-yl)acryloyl Azide

[1020] To a mixture of 1-benzyl-1H-pyrrole-2-carbaldehyde (28.4 g, 0.125mol) and TEA (13.5 mL, 0.187 mol) in acetone (300 mL) was addedethylchloroformate (17.9 mL, 0.87 mol) dropwise. The reaction wasstirred for 1.5 h after which NaN₃ (13 g, 0.200 mol) in H₂O (100 mL) wasadded. After 2 h, the reaction was diluted with water and leftovernight. The acetone was removed and the product was filtered off toafford 21.4 g of a light brown solid. This compound was taken to thenext step.

[1021] Intermediate 89

[1022] 1-Benzyl-1,5-dihydro-pyrrolo[3,2-c]pyridin-4-one was prepared bythe literature procedure according to C. Ducrocq; E. Bisangi; J-M,Lhoste; J. Mispelter; Tetrahedron, Vol 32, pp 773-780, (1976).

[1023] To a stirred solution of n-tributylamine (30 mL) in diphenylether (150 mL) heated to 195° C. was slowly added during 30 minutes asolution of the acyl azide dissolved in DCM (150 mL). The reactionmixture was stirred at 195° C. for 1 hour and then cooled to roomtemperature. Pentane (1.0 L) and ether (1.0 L) was added to the reactionmixture and the precipitate was collected by filtration. The crude solidwas triturated with ether to give 6.89 g (81%) of the pure product.Purity HPLC>95%; MS (ESI) m/z 225 (m+H); ¹H NMR (DMSO-d6, 25° C.,270.16) δ 10.84 (br s, 1H), 7.43-7.14 (m, 6H), 7.00 (d, J=7.12 Hz, 1H),6.57-6.49 (m, 2H), 5.83 (s, 2H).

[1024] Intermediate 90

[1025] 1-Benzyl-4-chloro-1H-indole

[1026] POCl₃ (3.11 mL, 33.4 mmol) was added to1-benzyl-1,5-dihydro-4H-pyrrolo[3,2-c]pyridin-4-one (3.75 g, 16.7 mmol)and the reaction was stirred at 120° C. for 2 h. NaOH (1M) was added andthe mixture was extracted with DCM three times. The organic layers weredried (MgSO₄), filtered and the solvent was removed. Flashchromatography (DCM/Heptane/MeOH 4:15:1) gave 1.17 g (29%) of product.The product was taken to the next step.

[1027] Intermediate 91

[1028] tert-Butyl4-(1-benzyl-1H-pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate

[1029] A mixture of 1-benzyl-4-chloro-1H-indole (1.17 g, 4.82 mmol),K₂CO₃ (2.0 g, mmol) and Boc-piperazine (1.79 g, 9.64 mmol) in DMSO (75mL) was stirred at 120° C. for 48 h. Additional of Boc-piperazine (4equiv.) was added and the reaction was run for another 48 h. Thereaction was diluted with ethyl acetate (200 mL) and the mixture waswashed with several portions of water. Flash chromatography(DCM/MeOH/Heptane 4:1:15) gave 0.51 g of starting material and 0.38 g ofproduct. ¹HNMR (CD₃OD) δ 7.87-7.85 (m, 1H), 7.25-7.24 (m, 3H), 7.04-6.98(m, 3H), 6.73-6.71 (m, 1H), 6.53-6.52 (m, 1H), 5.19 (s, 2H), 3.63-3.59(m, 8H), 1.47 (s, 9H); MS (ESI) 393 (M+H)⁺; Purity (HPLC, column ACE)95%

[1030] Intermediate 92

[1031] tert-Butyl4-(1H-pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate

[1032] tert-Butyl4-(1-benzyl-1H-pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate (383mg, 0.488 mmol) was dissolved in THF (6 mL) and liquid ammonia (10 mL)in a 30 mL vial. Na (67 mg, 2.93 mmol) was added in portions and thereaction turned violet. After 30 min NH₄Cl (sat) was added and thereaction was let to room temperature The THF was removed and the residuewas extracted with DCM. Recrystallization (DCM/Heptane) gave 112 mg of awhite solid. ¹HNMR (CD₃OD) δ 8.66 (s, 1H), 7.89 (d, 1H, J=5.80 Hz),7.13-7.11 (m, 1H), 6.89-6.86 (m, 1H), 6.57-6.56 (m, 1H), 3.67-3.60 (m,8H), 1.48 (s, 9H); MS (ESI) 303 (M+H)⁺; Purity (HPLC, column ACE) 95%.

[1033] Method S for sulphonylation: tert-butyl4-(1H-pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate (total 1.391mmol, 1 equiv.) dissolved in THF (14 mL) and dispense to 10 mL vialswith screwcap. A suspension of NaH (0.1488 mmol, 1.5 equiv.) in THF (15mL) was dispense evenly to the vials containing the solution oftert-butyl 4-(1H-pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate andstired for approximately for 15 min. Different sulfonylchlorides weredissolved in THF (2 mL) each and added drop-wise to the reactionmixtures. The reactions were quenched with MeOH (100 μL) andPS-Trisamine (3 equiv.) was added to each vial and shake for 2 hours.The mixtures were filtered and the filtrates were concentrate undervacuum. The products that were not pure enough (Purity <90%) werepurified by preparative chromatography using acetonitrile-watergradients containing 0.1% triflouroacetic acid. After HPLC analysisfractions that were ≧90% pure were collected and concentrated.

[1034] Method T BOC deprotection; The Boc-protected compound wasdissolved in MeOH (2 mL) and HCL/ether (2 mL) was added. After 45 minthe solvent was removed.

[1035] Intermediate 93

[1036]tert-Butyl-4-[1-(phenylsulfonyl)-1H-pyrrolo[3,2-c]pyridin-4-yl]piperazine-1-carboxylate

[1037] Purification by recrystallization gave 16 mg (56%) afterBoc-deprotection.

[1038]¹HNMR (CDCl₃) δ 8.03-8.01 (m, 1H), 7.89-7.86 (m, 2H), 7.57-7.39(m, 5H), 6.67-6.64 (m, 1H), 3.55-3.52 (m, 8H), 1.47 (s, 9H); MS (ESI)443 (M+H)⁺; Purity (HPLC, column ACE) 95%.

[1039] Intermediate 94

[1040]tert-Butyl-4-{1-[(4-chlorophenyl)sulfonyl]-1H-pyrrolo[3,2-c]pyridin-4-yl}piperazine-1-carboxylate

[1041] Purification by preparative HPLC gave 4 mg (11%) afterBoc-deprotection.

[1042]¹HNMR (CDCl₃) δ 8.03-7.51 (m, 7H), 6.89-6.87 (m, 1H), 3.91-3.66(m, 8H), 1.47 (s, 9H); MS (ESI) 377 (M+H)⁺; Purity (HPLC, column ACE)95%.

[1043] Intermediate 95

[1044]tert-Butyl-4-{1-[(4-methoxyphenyl)sulfonyl-1H-pyrrolo[3,2-c]pyridin-4-yl}piperazine-1-carboxylate

[1045] Purification by recrystallization (MeOH/Ether) gave 21 mg (67%)after boc-deprotection.

[1046]¹HNMR (CDCl₃) δ 8.02-8.00 (m, 1H), 7.84-7.80 (m, 2H), 7.48-7.46(m, 1H), 7.41-7.38 (m, 1H), 6.92-6.86 (m, 2H), 6.64-6.62 (m, 1H), 3.79(s, 3H), 3.57-3.52 (m, 8H), 1.48 (s, 9H); MS (ESI) 473 (M+H)⁺; Purity(HPLC, column ACE) 95%.

[1047] Intermediate 96

[1048] tert-Butyl4-(1-{[2-(trifluoromethyl)phenyl]sulfonyl}-1H-pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate

[1049] Purification by preparative HPLC gave 8.6 mg (25%) afterboc-deprotection. ¹HNMR (CDCl₃) δ 8.14-8.11 (m, 1H), 8.01-7.94 (m, 2H),7.89-7.72 (m, 3H), 7.37-7.34 (m, 1H), 6.89-6.88 (m, 1H), 3.93-3.89 (m,4H), 3.71-3.67 (m, 4H), 1.47 (s, 9H); MS (ESI) 511 (M+H)⁺; Purity (HPLC,column ACE) 95%.

[1050] Intermediate 97

[1051] tert-Butyl4-{1-[(2-methoxy-5-methylphenyl)sulfonyl]-1H-pyrrolo[3,2-c]pyridin-4-yl}piperazine-1-carboxylate

[1052] Purification by preparative HPLC gave 10.3 mg (32%) afterboc-deprotection. ¹HNMR (CDCl₃) δ 7.95-7.92 (m, 2H), 7.74-7.72 (m, 1H),7.44-7.40 (m, 2H), 6.85-6.77 (m, 2H), 3.92-3.88 (m, 4H), 3.70 (s, 3H),3.69-3.66 (m, 4H), 2.39 (s, 3H), 1.47 (s, 9H); MS (ESI) 487 (M+H)⁺;Purity (HPLC, column ACE) 95%.

EXAMPLE 121

[1053] 4-Piperazin-1-yl-1-(toluene-4-sulfonyl)-1H-pyrrolo[3,2-c]pyridineHydrochloride

[1054] p-Toulenesulfonyl chloride (24.6 mg) was added to tert-butyl4-(1H-pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate the titlecompound (4.3 mg). LC/MS R_(T): 1.374 (System 10 till 40% MeCN over 1.5min, ACE C8), Purity. 91%. MS: 357 (M+1) ¹HNMR (CD₃OD) δ ppm 2.39 (s,3H) 3.48 (m, 4H) 4.06 (m, 4H) 7.22 (d, J=3.71 Hz, 1H) 7.43 (d, J=8.16Hz, 2H) 7.95 (m, 5H).

EXAMPLE 122

[1055]1-(3-Chloro-2-methyl-benzenesulfonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridineHydrochloride

[1056] 3-Chloro-2-methylbenzenesulfonyl chloride (29.0 mg) was added totert-butyl 4-(1H-pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate thetitle compound (6.3 mg). LC/MS R_(T): 1.563 (System 10 till 40% MeCNover 1.5 min, ACE C8), Purity. 96%. MS: 392 (M+1).

EXAMPLE 123

[1057]1-(3,4-Dimethoxy-benzenesulfonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridineHydrochloride

[1058] 3,4-Dimethoxybenzenulfonyl chloride (30.5 mg) was added totert-butyl 4-(1H-pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate thetitle compound (8.5 mg). LC/MS R_(T): 1.284 (System 10 till 40% MeCNover 1.5 min, ACE C8), Purity. 92%. MS: 404 (M+1) ¹HNMR (CD₃OD) δ ppm3.50 (m, J=4.21 Hz, 2H) 3.85 (d, J=3.22 Hz, 4H) 4.10 (m, J=3.96 Hz, 2H)7.11 (d, J=8.66 Hz, 1H) 7.23 (d, J=3.46 Hz, 1H) 7.48 (d, J=1.73 Hz, 1H)7.74 (dd, J=8.54, 1.86 Hz, 1H) 7.92 (s, 2H) 8.07 (d, J=3.46 Hz, 1H).

EXAMPLE 124

[1059]4-(4-Piperazin-1-yl-pyrrolo[3,2-c]pyridine-1-sulfonyl)-benzonitrileHydrochloride

[1060] 4-Cyanobenzenesulfonyl chloride (26.0 mg) was added to tert-butyl4-(1H-pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate the titlecompound (9.1 mg). LC/MS R_(T): 1.150 (System 10 till 40% MeCN over 1.5min, ACE C8), Purity. 93%. MS: 369 (M+1) ¹HNMR (CD₃OD) δ ppm 3.50 (m,4H) 4.08 (m, 4H) 7.29 (d, J=3.71 Hz, 2H) 7.98 (m, 4H) 8.29 (d, J=8.66Hz, 2H).

EXAMPLE 125

[1061]1-(4,5-Dichloro-thiophene-2-sulfonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridineHydrochloride

[1062] 4,5-Dichloro-thiophene-2-sulfonyl chloride (32.4 mg) was added totert-butyl 4-(1H-pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate thetitle compound (0.3 mg). LC/MS R_(T): 1.119 (System 10 till 40% MeCNover 1.5 min, ACE C8), Purity. 92%. MS: 418 (M+1).

EXAMPLE 126

[1063]1-(2-Chloro-4-fluoro-benzenesulfonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridineHydrochloride

[1064] 2-Chloro-4-flourobenzenesulfonyl chloride (29.5 mg) was added totert-butyl 4-(1H-pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate thetitle compound (2.4 mg). LC/MS R_(T): 1.361 (System 10 till 40% MeCNover 1.5 min, ACE C8), Purity. 90%. MS: 396 (M+1)

[1065]¹HNMR (CD₃OD) δ ppm 3.51 (m, 4H) 4.08 (m, 4H) 7.23 (dd, J=3.96,0.49 Hz, 1H) 7.47 (m, 1H) 7.55 (dd, J=8.41, 2.47 Hz, 2H) 7.62 (d, J=6.93Hz, 1H) 7.91 (d, J=7.18 Hz, 1H) 8.06 (d, J=3.96 Hz, 1H).

EXAMPLE 127

[1066] 1-Phenylmethanesulfonyl-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridine Hydrochloride

[1067] Phenyl-methanesulfonyl chloride (24.6 mg) was added to tert-butyl4-(1H-pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate the titlecompound (0.2 mg). LC/MS R_(T): 1.007 (System 10 till 40% MeCN over 1.5min, ACE C8), Purity. 90%. MS: 357 (M+1).

EXAMPLE 128

[1068]1-(5-Chloro-thiophene-2-sulfonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridineHydrochloride

[1069] 5-Chlorothiophene-2-sulfonyl chloride (28.0 mg) was added totert-butyl 4-(1H-pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate thetitle compound (7.2 mg). LC/MS R_(T): 1.381 (System 10 till 40% MeCNover 1.5 min, ACE C8), Purity. 97%. MS: 483 (M+1).

EXAMPLE 129

[1070]1-(4-Butyl-benzenesulfonyl)-4-piperazin-1-yl-1H-pyrrolo(3,2-c)pyridineHydrochloride

[1071] 4-N-Butylbenzenesulfonylchloride (30.0 mg) was added totert-butyl 4-(1H-pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate thetitle compound (11.9 mg). LC/MS R_(T): 1.904 (System 10 till 40% MeCNover 1.5 min, ACE C8), Purity. 95%. MS: 400 (M+1) ¹HNMR (CD₃OD) δ ppm0.90 (t, J=7.18 Hz, 3H) 1.31 (m, 2H) 1.55 (m, 2H) 2.67 (m, 2H) 3.50 (m,4H) 4.09 (m, J=3.96 Hz, 4H) 7.25 (d, J=3.71 Hz, 2H) 7.44 (d, J=8.16 Hz,2H) 7.91 (m, 2H) 8.02(m, 2H).

EXAMPLE 130

[1072] 1-(4-Phenoxy-benzenesulfonyl)-4-piperazin-1-yl-1H-pyrrolo(3,2-c)pyridine Hydrochloride

[1073] (4-Phenoxy)benzene)sulfonyl chloride (34.7 mg) was added totert-butyl 4-(1H-pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate thetitle compound (12.8 mg). LC/MS R_(T): 1.839 (System 10 till 40% MeCNover 1.5 min, ACE C8), Purity. 95%. MS: 436 (M+1) ¹HNMR (CD₃OD) δ ppm3.50 (m, J=3.96 Hz, 4H) 4.09 (m, J=4.45 Hz, 4H) 7.05 (dd, J=8.16, 6.43Hz, 2H) 7.26 (m, 2H) 7.44 (t, J=7.79 Hz, 2H) 7.90 (m, 3H) 8.01 (d,J=3.71 Hz, 2H) 8.07 (d, J=8.91 Hz, 2H).

EXAMPLE 131

[1074] 1-(Phenylsulfonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridineHydrochloride

[1075] Purification by recrystallization gave 16 mg (56%) afterBoc-deprotection. MS (ESI) 343.1 (M+H)⁺; Purity (HPLC, column ACE) 94%.

EXAMPLE 132

[1076]1-[(4-Chlorophenyl)sulfonyl]-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridineHydrochloride

[1077] Purification by preparative HPLC gave 4 mg (11%) afterBoc-deprotection. MS (ESI) 377 (M+H)⁺; Purity (HPLC, column ACE) 96%.

EXAMPLE 133

[1078]1-[(4-Methoxyphenyl)sulfonyl]-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridineHydrochloride

[1079] Purification by recrystallization (MeOH/Ether) gave 21 mg (67%)after Boc-deprotection. MS (ESI) 373 (M+H)⁺; Purity (HPLC, column ACE)92%

EXAMPLE 134

[1080]1-[(2-Methoxy-5-methylphenyl)sulfonyl]-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridineHydrochloride

[1081] Purification by preparative HPLC gave 10.3 mg (32%) afterBoc-deprotection. MS (ESI) 387 (M+H)⁺; Purity (HPLC, column ACE) 95%.

EXAMPLE 135

[1082]4-Piperazin-1-yl-1-{[2-(trifluoromethyl)phenyl]sulfonyl}-1H-pyrrolo[3,2-c]pyridineHydrochloride

[1083] Purification by preparative HPLC gave 8.6 mg (25%) afterBoc-deprotection. MS (ESI) 411 (M+H)⁺; Purity (HPLC, column ACE) 94%.

[1084] Biological Tests

[1085] The ability of a compound according to the invention to bind a5-HT₆ receptor, and to be pharmaceutically useful, can be determinedusing in vivo and in vitro assays known in the art.

[1086] (a) 5-HT₆ Binding Assay

[1087] Binding affinity experiment for the 5-HT₆ receptor are performedin HEK293 cells transfected with 5-HT₆ receptor using (3H)-LSD aslabeled ligand according to the general method as described by Boess F.G et al. Neuropharmacology vol. 36(4/5) 713-720, 1997.

[1088] Materials

[1089] Cell Culture

[1090] The HEK-293 cell line transfected with the 5-HT₆ receptor wascultured in Dulbeccos Modified Eagles Medium containing 5% dialyzedfoetal bovine serum, (Gibco BRL 10106-169), 0.5 mM sodium pyruvate and400 μg/ml Geneticin (G-418) (Gibco BRL10131-019). The cells werepassaged 1:10, twice a week.

[1091] Chemicals

[1092] The radioligand [³H] LSD 60-240 Ci/mmol, obtained from AmershamPharmacia Biotech, (Buckinghamshire, England) was in ethanol and storedat −20° C. The unlabelled ligands, representing different selectivityprofiles, are presented in Table 1. The compounds were dissolved in 100%DMSO and diluted with binding buffer.

[1093] Disposable

[1094] Compounds were diluted in Costar 96 well V-bottom polypropyleneplates (Corning Inc. Costar, N.Y., USA). Samples were incubated inPackard Optiplate (Packard Instruments B. V., Groningen, TheNetherlands). The total amount of added radioligand was measured inPackard 24-well Barex plates (Packard Instruments B. V., Groningen, TheNetherlands) in the presence of Microscint™ 20 scintillation fluid(Packard Bioscience, Meriden, Conn., USA).

[1095] Buffer

[1096] The binding buffer consisted of 20 mM HEPES, 150 mM NaCl, 10 mMMgCl₂, and 1 mM, EDTA, pH 7.4.

[1097] Methods

[1098] Membrane Preparation

[1099] Cells were grown to approximately 90% confluence on 24.5×24.5NUNC culture dishes. The medium was aspirated, and after rinsing withice-cold PBS, the cells were scraped off using 25 ml Tris buffer (50 mMTris-HCl, 1 mM EDTA, 1 mM EGTA, pH 7.4) and a window scraper. The cellswere then broken with a Polytron homogeniser, and remaining particulatematter was removed by low-speed centrifugation, 1000×g for 5 min.Finally, the membranes were collected by high-speed centrifugation (20000×g), suspended in binding buffer, and frozen in aliquots at −70° C.

[1100] Radioligand Binding

[1101] Frozen cell membranes were thawed, immediately rehomogenized witha Polytron homogenizer, and coupled to SPA wheat germ agglutinin beads(Amersham Life Sciences, Cardiff, England) for 30 min under continuousshaking of the tubes. After coupling, the beads were centrifuged for 10minutes at 1000 g, and subsequently suspended in 20 ml of binding bufferper 96-well plate The binding reaction was then initiated by addingradioligand and test compounds to the bead-membrane suspension.Following incubation at room temperature, the assay plates weresubjected to scintillation counting.

[1102] The original SPA method was followed except for that membraneswere prepared from HEK293 cells expressing the human 5-HT₆ receptorinstead of from HeLa cells (Dinh D M, Zaworski P G, Gill G S, SchlachterS K, Lawson C F, Smith M W. Validation of human 5-HT₆ receptorsexpressed in HeLa cell membranes: saturation binding studies,pharmacological profiles of standard CNS agents and SPA development. TheUpjohn Company Technical Report 7295-95-064 1995;27 December). Thespecific binding of [³H]LSD was saturable, while the non-specificbinding increased linearly with the concentration of added radioligand.[³H] LSD bound with high affinity to 5-HT₆ receptors. The K_(d) valuewas estimated to 2.61 0.2 nM based on four separate experiments.

[1103] The total binding at 3 nM of [³H] LSD, the radioligandconcentration used in the competition experiments, was typically 6000dpm, and the specific binding more than 70%. 5-HT caused a concentrationdependent inhibition of [³H] LSD binding with an over all average Kivalue of 236 nM when tested against two different membrane preparations.The inter assay variability over three experiments showed a CV of 10%with an average K_(i) values of 173 nM (SD 30) and a Hill coefficient of0.94 (SD 0.09). The intra assay variation was 3% (n—4). Ki values for alimited set of reference compounds with reported binding affinities at5-HT₆ receptor are presented in Table 7. All unlabelled ligandsdisplaced the specific binding of [³H] LSD in a concentration-dependentmanner, albeit at different potencies. The rank order of potency for thecompounds was methiothepin (2 nM)>mianserin (190 nM)≈5-HT (236nM)>methysergide (482 nM)>mesulergide (1970 nM).

[1104] Protein Determination

[1105] Protein concentrations were determined with BioRad Protein Assay(Bradford MM. A rapid and sensitive method for the quantitation ofmicrogram quantities of protein utilizing the principle of protein-dyebinding. Anal Biochem 1976;72:248-54). Bovine serum albumin was used asstandard.

[1106] Scintillation Counting

[1107] The radioactivity was determined in a Packard TopCount™scintillation counter (Packard Instruments, Meriden, Conn., USA) at acounting efficiency of approximately 20%. The counting efficiency wasdetermined in separate sets of experiments.

[1108] Saturation Experiments

[1109] At least 6 concentrations in duplicates of radioligand (0.1-20 nMof [³H] LSD) were used in saturation experiments. The specific bindingwas calculated as the difference between total binding and non-specificbinding, which was determined as the binding of radioligand in thepresence of 5 μM lisuride. B_(max) and the dissociation constant, K_(d),were determined from the non-linear regression analysis usingequation 1. L_(u) is the unbound concentration of radioligand, and is yis the amount bound. $\begin{matrix}{y = \frac{B_{\max} \cdot {Lu}}{{Lu} + {Kd}}} & \text{(equation~~1)}\end{matrix}$

[1110] Competition Experiments

[1111] Total- and non-specific binding of radioligand was defined ineight replicates of each. Samples containing test compound were run induplicate at 11 concentrations. Incubations were carried out at roomtemperature for 3 hours. The IC₅₀ value, i.e. the concentration of testcompound that inhibited 50% of the specific binding of radioligand, wasdetermined with non linear regression analysis and the K_(i) value wascalculated using the method of [Cheng Y. C. Biochem. Pharmacol. 22,3099-3108, 1973S] equation 2. $\begin{matrix}{{Ki} = \frac{{IC}_{50}}{1 + \frac{L}{K_{d}}}} & \text{(equation~~2)}\end{matrix}$

[1112] L=concentration of radioligand

[1113] K_(d)=Affinity of radioligand

[1114] (b) 5-HT₆ Intrinsic Activity Assay

[1115] Antagonists to the 5-HT₆ receptor were characterized by measuringinhibition of 5-HT induced increase in cAMP in HEK 293 cells expressingthe human 5-HT₆ receptor (see Boess et al. (1997) Neuropharmacology 36:713-720). Briefly, HEK293/5-HT₆ cells were seeded in polylysine coated96-well plates at a density of 25,000/well and grown in DMEM (Dulbecco'sModified Eagle Medium) (without phenol-red) containing 5% dialyzedFoetal Bovine Serum for 48 h at 37° C. in a 5% CO₂ incubator. The mediumwas then aspirated and replaced by 0.1 ml assay medium (Hanks BalanceSalt Solution containing 20 mM HEPES, 1.5 mM isobutylmethylxanthine and1 mg/ml bovine serum albumin). After addition of test substances, 50 μldissolved in assay medium, the cells were incubated for 10 min at 37° C.in a 5% CO₂ incubator. The medium was again aspirated and the cAMPcontent was determined using a radioactive cAMP kit (Amersham PharmaciaBiotech, BIOTRAK RPA559). The potency of antagonists was quantified bydetermining the concentration that caused 50% inhibition of 5-HT (at[5-HT]=8 times EC₅₀) evoked increase in cAMP, using the formulaIC50,corr =IC₅₀/(1+[5HT]/EC₅₀).

[1116] The compounds in accordance with the invention have a selectiveaffinity to 5-HT₆ receptors with K_(i) and IC_(50,corr) values between0.5 nM and 5 μM or display a % inhibition of [³H] LSD≧20% at 50 nM andare antagonists, agonist or partial agonist at 5-HT₆. The compounds showgood selectivity over 5-HT_(1a), 5-HT_(2a), 5-HT_(2a), 5-HT_(2b),5-HT_(2c).

[1117] (c) In Vivo Assay of Reduction of Food Intake

[1118] For a review on serotonin and food intake, see Blundell, J. E.and Halford, J. C. G. (1998) Serotonin and Appetite Regulation.Implications for the Pharmacological Treatment of Obesity. CNS Drugs9:473-495.

[1119] Obese (ob/ob) mouse is selected as the primary animal model forscreening as this mutant mouse consumes high amounts of food resultingin a high signal to noise ratio. To further substantiate and compareefficacy data, the effect of the compounds on food consumption is alsostudied in wild type (C57BL/6J) mice. The amount of food consumed during15 hours of infusion of compounds is recorded.

[1120] Male mice (obese C57BL/6JBom-Lep^(ob) and lean wild-typeC57B1/6JBom; Bomholtsgaard, Denmark) 8-9 weeks with an average bodyweight of 50 g (obese) and 25 g (lean) are used in all the studies. Theanimals are housed singly in cages at 23±1° C., 40-60% humidity and havefree access to water and standard laboratory chow. The 12/12-hlight/dark cycle is set to lights off at 5 p.m. The animals areconditioned for at least one week before start of study.

[1121] The test compounds are dissolved in solvents suitable for eachspecific compound such as cyclodextrin, cyclodextrin/methane sulfonicacid, polyethylene glycol/methane sulfonic acid, saline. Fresh solutionsare made for each study. Doses of 30, 50 and 100 mg kg⁻¹day⁻¹ are used.The purity of the test compounds is of analytical grade.

[1122] The animals are weighed at the start of the study and randomizedbased on body weight. Alzet osmotic minipumps (Model 2001D; infusionrate 8 μl/h) are used and loaded essentially as recommended by the Alzettechnical information manual (Alza Scientific Products, 1997; Theeuwes,F. and Yam, S. I. Ann. Biomed. Eng. 4(4). 343-353, 1976). Continuoussubcutaneous infusion with 24 hours duration is used. The minipumps areeither filled with different concentrations of test compounds dissolvedin vehicle or with only vehicle solution and maintained in vehiclepre-warmed to 37° C. (approx. 1 h). The minipumps are implantedsubcutaneously in the neck/back region under short acting anesthesia(metofane/enflurane).

[1123] This surgical procedure lasts approximately 5 min. It takes about3 h to reach steady state delivery of the compound.

[1124] The weight of the food pellets are measured at 5 p.m. and at 8p.m. for two days before (baseline) and one day after the implantationof the osmotic minipumps. The weigh-in is performed with a computerassisted Mettler Toledo PR 5002 balance. Occasional spillage iscorrected for. At the end of the study the animals are killed by neckdislocation and trunk blood sampled for later analysis of plasma drugconcentrations.

[1125] The plasma sample proteins are precipitated with methanol,centrifuged and the supernatant is transferred to HPLC vials andinjected into the liquid chromatography/mass spectrometric system. Themass spectrometer is set for electrospray positive ion mode and MultipleReaction Monitoring. A linear regression analysis of the standardsforced through the origin is used to calculate the concentrations of theunknown samples.

[1126] Food consumption for 15 hours is measured for the threeconsecutive days and the percentage of basal level values is derived foreach animal from the day before and after treatment. The values areexpressed as mean±SD and ±SEM from eight animals per dose group.Statistical evaluation is performed by Kruskal-Wallis one-way ANOVAusing the percent basal values. If statistical significance is reachedat the level of p<0.05, Mann-Whitney U-test for statistical comparisonbetween control and treatment groups is performed.

[1127] The compounds according to the invention show an effect in therange of 5-200 mg/kg. TABLE 7 Biological data In vitro binding at thehuman 5-HT6 receptor K_(i) (nM) EXAMPLE human 5-HT₆ 1 10 11 6.5 20 10.540 7.5 43 4.5 68 13 85 32 131 5 In vivo efficacy data EXAMPLE % FIreduction* Css, u (uM) 1 12 0.44 11 47.1 0.02 40 44 0.2

1. A compound of the formula (I):

or a pharmaceutically acceptable salt thereof, wherein: ring B is

 in which D is a five-membered heterocyclic or heteroaryl ring, saidring comprising one or two atoms selected from the group consisting ofnitrogen, sulfur and oxygen, with the proviso that when D contains anoxygen atom, D is heteroaryl; each W is independently —N—, —(CH)—, or—C— provided that not more than three groups W are —N— in both rings Aand B together; P is any one of formula (a), (b) or (c)

wherein x 0, 1, or 2 and y=0, 1, or 2; and P and R³ can be attached toany carbon atom that allows the substitution in one of either the A- orB-ring, or when ring A contains at least one nitrogen atom and P is (c),then P can also be attached to any nitrogen in ring B that allows thesubstitution; the dashed bonds denote that P and R³, respectively, maybe attached to either the A or B ring; but each P or R³ may not besimultaneously bound to both rings A and B; R¹ is (a) C₁₋₆ alkyl, (b)C₁₋₆ alkoxyalkyl, (c) straight-chained or branched C₁₋₆ hydroxyalkyl,(d) straight-chained or branched C₁₋₆ alkylhalides, (e) arylcarbonylmethyl, (f) C₃₋₇ cycloalkyl, which is optionally partiallyunsaturated, (g) C₃₋₇ cycloalkyl-C₁₋₆ alkyl, wherein the cyclic ring isoptionally partially unsaturated, or (h) a group Ar; wherein Ar is (a)phenyl, (b) 1-naphthyl, (c) 2-naphthyl, (d) aryl-C₁₋₆ alkyl, (e)cinnamyl, (f) a 5 to 7-membered, optionally aromatic, partiallysaturated or completely saturated, mono- or bi-cyclic heterocyclic ring,each containing 1 to 4 heteroatoms, selected from oxygen, sulfur, andnitrogen, (g) a bicyclic ring system comprising at least oneheterocyclic ring according to (f) and a group Ar, wherein the group Aris substituted in one or more positions with (a) H, X or Y, or (b) a 5to 7-membered, optionally aromatic, partially saturated or completelysaturated, heterocyclic ring each containing 1 to 4 heteroatoms selectedfrom oxygen, nitrogen or sulfur; R¹ is (a) H, (b) C₁₋₆ alkyl, (c) C₂₋₆alkoxyalkyl, (d) straight or branched C₁₋₆ hydroxyalkyl, or (e) straightor branched C₁₋₆ alkylhalides; (f) a group Ar, or R¹ and R² are linkedto form a group —CH₂CH₂OCH₂CH₂— or

wherein v is 0-2, X and Y are independently (a) H, (b) halogen, (c) C₁₋₆alkyl, (d) CF₃, (e) hydroxy, (f) C₁₋₆ alkoxy, (g) C₂₋₆ alkenyl, (h)phenyl, (i) phenoxy, (j) benzyloxy, (k) benzoyl, (l) —OCF₃, (m) —CN, (n)straight or branched C₁₋₆ hydroxyalkyl, (o) straight or branched C₁₋₆alkylhalides, (p) —NH₂, (q) —NHR⁴, (r) —NR⁴R⁵, (s) —NO₂, (t) —CONR⁴R⁵,(u) —NHSO₂R⁴, (v) —NR⁴COR⁵, (x) —SO₂NR⁴R⁵, (z) —C(═O)R⁴, (aa) —CO₂R⁴, or(ab) —S(O)_(n)R⁴, wherein n is 0, 1, 2 or 3, (ac) —S—(C₁₋₆) alkyl, or(ad) —SCF₃; and R⁴ and R⁵ are independently (a) H, (b) C₁₋₆ alkyl, (c)C₃₋₇ cycloalkyl, or (d) Ar, as defined above for R¹; alternatively, R⁴and R⁵ are linked to form a group —CH₂OCH₂—, —CH₂CH₂OCH₂CH₂— or(CH₂)₃₋₅; R³ is a group selected from any one of

wherein R³ is optionally substituted on each carbon atom that allows thesubstitution with Rq groups, wherein Rq is independently H, or (C₁₋₆)alkyl, and wherein two Rq groups can be present on the same carbon atomsimultaneously, wherein q=1, 2, 3, 4, 5 or 6, m=1 or 2, and n=0, 1 or 2;R⁶ is independently (a) H, (b) linear or branched C₁₋₆ alkyl, (c)benzyl, (d) —CH₂—CH₂—OH, or (e) —CH₂—CH₂—O—C₁₋₆ alkyl; P and R³ can beattached to the same ring or to different rings of rings A and B;provided that when P is

 P and R both are attached to ring A in the meta- or para-positionrelative to one another then R³ is selected from any one of

when ring B is

 and P is

 then P and R³ are simultaneously attached to the same ring A or B; whenring B is

 and P is

 wherein y=0, then P and R³ are attached to the different rings of ringsA and B; when the ring system A+B is benzofurane or benzothiophene, andP is

and attached to position 3 in the A+B ring system, and R³ is a groupselected from any one of

and attached to position 7 in the A+B ring system, then y=1 or 2; whenthe ring system A+B is indole, and P is

and P is attached to position 3 in the A+B ring system, and R³ is agroup selected from any one of

and R³ is attached to any one of positions 5, 6 or 7 in the A+B ringsystem, then y=1 or 2; or when ring B is

 and R¹=Ar is partially saturated bi-cyclic heterocyclic ring containinga N atom, the N atom in Ar cannot be attached to the S atom in P; withthe proviso that: when rings A and B are both phenyl, P is any one offormula (a) or (c) substituted in position 7 on the naphthalene ring,then R³ is not substituted in position 1 on the naphthalene ring; andwith the proviso that: when ring D is a pyrrole ring, P is of theformula (c), then R³ is not of the formula

substituted in position 3 on the pyrrole ring.
 2. The compound accordingto claim 1, wherein R¹ is (a) C₁₋₆ alkyl, or (e) a group Ar; Ar is (a)phenyl, (b) 1-naphthyl, (c) 2-naphthyl, or (f) a 5 to 7-membered,optionally aromatic, partially saturated or completely saturated,heterocyclic ring containing 1 to 4 heteroatoms, selected from oxygen,nitrogen and sulfur, wherein the group Ar is substituted in one or morepositions with (a) H, (b) halogen, (c) C₁₋₆ alkyl, (d) —CF₃, (f) C₁₋₆alkoxy, (g) C₂₋₆ alkenyl, (l) —OCF₃, (m) straight or branched C₁₋₆hydroxyalkyl, (n) phenyloxy, (0) benzyloxy, (v) —NR⁴COR⁵, (x) —SO₂NR⁴R⁵,(z) —C(═O)R⁴, (ab) —S(O)_(n)R⁴, wherein n is 0, 1, 2 or 3; (ac)—S—(C₁₋₆) alkyl, or (ad) —SCF₃; R² is (a) H, or (b) C₁₋₆ alkyl; or R¹and R² are linked to form a group —CH₂CH₂OCH₂CH₂—; X and Y are H; R⁴ andR⁵ are each independently H or C₁₋₃ alkyl; and R³ is selected from anyone of

wherein R³ can be substituted on each carbon atom that allows thesubstitution with Rq groups, wherein Rq is independently H, or C₁₋₆alkyl, and wherein two Rq groups can be present on the same carbon atomsimultaneously, wherein q=or 2, m=1 or 2, n=0, and R⁶ is independently(a) H, (b) C₁₋₆ alkyl, in particular methyl, (d) —CH₂—CH₂—OH, or (e)—CH₂—CH₂—OCH₃.
 3. The compound of claim 1, wherein R³ is selected from:

wherein R³ can be substituted on each carbon atom that allows thesubstitution with Rq groups, wherein Rq is independently H, or C₁₋₂alkyl, and wherein two Rq groups can be present on the same carbon atomsimultaneously, wherein q=1 or 2, m=1 or 2; and R⁶ is independently (a)H, (b) C₁₋₃ alkyl, (d) —CH₂—CH₂—OH, or (e) —CH₂—CH₂—OCH₃.
 4. Thecompound of claim 1, wherein R³ is selected from:

wherein R³ can be substituted on each carbon atom that allows thesubstitution with Rq groups, wherein Rq is independently H, or C₁₋₆alkyl, and wherein two Rq groups can be present on the same carbon atomsimultaneously, wherein q=1 or 2, m=1 or 2, n=0, and R⁶ is independently(a) H, (b) C₁₋₃ alkyl, (d) —CH₂—CH₂—OH, or (e) —CH₂—CH₂—OCH₃.
 5. Thecompound of claim 1, wherein R³ is selected from:

R⁶ is independently (a) H, (b) C₁₋₃ alkyl, (d) —CH₂—CH₂—OH, or (e)—CH₂—CH₂—OCH₃.
 6. The compound of claim 1, wherein R is H or methyl. 7.The compound of claim 1, wherein R³ is piperazine; homopiperazine;2,6-dimethylpiperazine; 3,5-dimethylpiperazine; 2,5-dimethylpiperazine;2-methylpiperazine; 3-methylpiperazine; 2,2-dimethylpiperazine;3,3-dimethylpiperazine; piperidine; 1,2,3,6-tetrahydro-pyrazine; or4-pyrrolidin-3-yloxy.
 8. The compound of claim 1, wherein the groups Yand X are attached to any unsubstituted carbon atom.
 9. The compound ofclaim 1, wherein D is pyrrolyl, thienyl or furanyl.
 10. The compound ofclaim 1, wherein P is

wherein R¹, x, and y are as defined in formula (I).
 11. The compound ofclaim 1, wherein P is


12. The compound of claim 11, wherein R² is H.
 13. The compound of claim10, wherein the compound is a compound having formula (II)

wherein R¹, x, y, X, and Y are as defined in formula (I), and R³ is

wherein R³ can be substituted on each carbon atom that allows thesubstitution with Rq groups, wherein Rq is independently H, or C₁₋₆alkyl, and wherein two Rq groups can be present on the same carbon atomsimultaneously, wherein q=1 or 2, m=1 or 2, n=0.
 14. The compound ofclaim 13, wherein y=0 and x=2
 15. The compound of claim 10, wherein thecompound is a compound having formula (III):

wherein R¹, x, y, X, and Y are as defined in formula (I), and R³ is.

wherein R³ can be substituted on each carbon atom that allows thesubstitution with Rq groups, wherein Rq is independently H, or C₁₋₆alkyl, and wherein two Rq groups can be present on the same carbon atomsimultaneously, wherein q=1 or 2, m=1 or 2, n=0.
 16. The compound ofclaim 15, wherein y=0 and x=2
 17. The compound of claim 10, wherein thecompound is a compound having formula (IV):

wherein R, x, y, X, and Y are as defined in formula (I), and R³ is,

wherein R³ can be substituted on each carbon atom that allows thesubstitution with Rq groups, wherein Rq is independently H, or C₁₋₆alkyl, and wherein two Rq groups can be present on the same carbon atomsimultaneously, wherein q=1 or 2, m=1 or 2, n=0, and wherein D is afive-membered heteroaryl ring, said ring comprising one or two atomsselected from the group consisting of nitrogen, sulfur and oxygen; andwhen the heteroaryl ring comprises one or two nitrogen atoms, a group R⁶is attached at any nitrogen atom which allows the substitution.
 18. Thecompound of claim 17, wherein D is a thiophene and P is attached to theD ring.
 19. The compound of claim 17, wherein D is pyrrole and P isattached to the nitrogen atom in the D ring.
 20. The compound of claim17, wherein D is furan and P is attached to the D ring.
 21. The compoundof claim 10, wherein the compound is a compound having formula (V)

wherein, R¹, x, y, X, Y, and R³ are as defined in formula (I), andwherein D is a five-membered heteroaryl ring, said heteroaryl ringcomprising one or two atoms selected from the group consisting ofnitrogen, sulfur and oxygen; and when the heteroaryl ring comprises oneor two nitrogen atoms, a group R⁶ is attached at any nitrogen atom whichallows the substitution.
 22. The compound of claim 11, wherein thecompound is a compound having formula (V)

wherein; X, Y, and R³ are as defined in formula (I), and wherein D is afive-membered heteroaryl ring, said heteroaryl ring comprising one ortwo atoms selected from the group consisting of nitrogen, sulfur andoxygen; and when the heteroaryl ring comprises one or two nitrogenatoms, a group R⁶ is attached at any nitrogen atom which allows thesubstitution.
 23. The compound of claim 11, wherein the compound is acompound having formula (VI)

wherein X and Y are as defined in formula (I), and R³ is

wherein R³ can be substituted on each carbon atom that allows thesubstitution with Rq groups, wherein Rq is independently H, or C₁₋₆alkyl, and wherein two Rq groups can be present on the same carbon atomsimultaneously, wherein q=1 or 2, m=1 or 2, n=0.
 24. The compound ofclaim 11, wherein the compound is a compound having formula (VII):

wherein X and Y are as defined in formula (I), and R³ is

wherein R³ can be substituted on each carbon atom that allows thesubstitution with Rq groups, wherein Rq is independently H, or C₁₋₆alkyl, and wherein two Rq groups can be present on the same carbon atomsimultaneously, wherein q=1 or 2, m=1 or 2, n=0.
 25. The compound ofclaim 11, wherein the compound is a compound having formula (VIII)

wherein X, Y, and R³ are as defined in formula (I).
 26. The compound ofclaim 11, wherein the compound is a compound having formula (IX)

wherein R⁷ in formula (IX) is: (a) H, (b) C₁₋₆ alkyl, (c) benzyl, (d)—CH₂—CH₂—OH, or (e) CH₂—CH₂—O—CH₃, and wherein X, Y, and R³ are asdefined in formula (I).
 27. The compound of claim 11, wherein thecompound is a compound having formula (X)

wherein X, Y, and R³ are as defined in formula (I).
 28. The compound ofclaim 12, wherein the compound is a compound having formula (XI)

wherein X and Y are as defined in formula (I), and R³ is

wherein R³ can be substituted on each carbon atom that allows thesubstitution with Rq groups, wherein Rq is independently H, or C₁₋₆alkyl, and wherein two Rq groups can be present on the same carbon atomsimultaneously, wherein q=1 or 2, m=1 or 2, n=0.
 29. The compound ofclaim 1, wherein the compound is a compound having formula (XII):

wherein P and R³ are attached to the same ring or to different rings ofrings A and B, and wherein A, B, Y, P, and R₃ are as defined in formula(I), or a pharmaceutically acceptable salt thereof.
 30. The compound ofclaim 13, wherein the compound is:6-Benzenesulfonyl-4-piperazin-1-yl-quinoline hydrochloride;6-[(2-Fluorophenyl)sulfonyl]-4-piperazin-1-ylquinoline hydrochloride;6-(1-Naphthylsulfonyl)-4-piperazin-1-ylquinoline hydrochloride;6-[(3,4-Dichlorophenyl)sulfonyl]-4-piperazin-1-ylquinolinehydrochloride;6-[(3,5-Dimethylphenyl)sulfonyl]-4-piperazin-1-ylquinolinehydrochloride;6-[(2-Chloro-6-methylphenyl)sulfonyl]-4-piperazin-1-ylquinolinehydrochloride; 6-[(4-Chlorophenyl)sulfonyl]-4-piperazin-1-ylquinolinehydrochloride;6-[(2-Methyl,4-tert-butyl-phenyl)sulfonyl]-4-piperazin-1-ylquinolinehydrochloride;6-[(3,4-Dimethylphenyl)sulfonyl]-4-piperazin-1-ylquinolinchydrochloride;6-[(2,3-Dichlorophenyl)sulfonyl]-4-piperazin-1-ylquinolinehydrochloride;6-[(4-tert-Butylphenyl)sulfonyl]-4-piperazin-1-ylquinolinehydrochloride; 6-[(4-Isopropylphenyl)sulfonyl]-4-piperazin-1-ylquinolinehydrochloride;(4-Piperazin-1-yl-6-{[4-(trifluoromethyl)phenyl]sulfonyl}quinolinehydrochloride;6-[(4-tert-Butylphenyl)sulfonyl]-4-(1,4-diazepan-1-yl)quinolinehydrochloride; or4-(1,4-Diazepan-1-yl)-6-[(4-isopropylphenyl)sulfonyl]quinolinehydrochloride.
 31. The compound of claim 15, wherein the compound is:7-(2-Chloro-6-methyl-benzenesulfonyl)-1-piperazin-1-yl-isoquinolinehydrochloride;7-(2-t-Butyl-benzenesulfonyl)-1-piperazin-1-yl-isoquinolinehydrochloride;7-(3,4-Dichloro-benzenesulfonyl)-1-piperazin-1-yl-isoquinolinehydrochloride;7-(2,4-Dimethyl-benzenesulfonyl)-1-piperazin-1-yl-isoquinolinehydrochloride;7-(2,5-Dimethyl-benzenesulfonyl)-1-piperazin-1-yl-isoquinolinehydrochloride;7-(p-Chloro-benzenesulfonyl)-1-piperazin-1-yl-isoquinolinehydrochloride; 7-Benzenesulfonyl-1-[1,4]diazepan-1-yl-isoquinoline,hydrochloride;7-(4-tert-Butyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinoline,hydrochloride;7-(2-Chloro-6-methyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinolinehydrochloride;7-(3,5-Dimethyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinolinehydrochloride;7-(3,4-Dichloro-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinolinehydrochloride;7-(4-Chloro-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinolinehydrochloride;7-(3,4-Dimethyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinolinehydrochloride;7-(2-tert-Butyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinolinehydrochloride; 7-Benzenesulfonyl-1-piperazin-yl-isoquinolinehydrochloride; or7-(4-tert-Butyl-benzenesulfonyl-1-piperazin-yl-isoquinolinehydrochloride
 32. The compound of claim 17, wherein the compound is:4-(1,4-Diazepan-1-yl)-2-(phenylsulfonyl)thieno[3,2-c]pyridinehydrochloride;4-(1,4-Diazepan-1-yl)-2-[(3,4-dichlorophenyl)sulfonyl]thieno[3,2-c]pyridinehydrochloride;4-(1,4-Diazepan-1-yl)-2-[4-tert-butylphenylsulfonyl)thieno[3,2-c]pyridinehydrochloride;4-(1,4-Diazepan-1-yl)-2-[4-tert-butylphenylsulfonyl)thieno[3,2-c]pyridinehydrochloride;4-(1,4-Diazepan-1-yl)-2-[3,4-dimethylphenylsulfonyl)thieno[3,2-c]pyridinehydrochloride;2-[(4-Bromophenyl)sulfonyl]-4-(1,4-diazepan-1-yl)thieno[3,2-c]pyridinehydrochloride; 2-(Phenylsulfonyl)-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;2-(3-Methoxy-benzenesulfonyl)-4-piperazin-1-yl-thieno[3,2-c]pyridinehydrochloride;2-(4-Methoxy-benzenesulfonyl)-4-piperazin-1-yl-thieno[3,2-c]pyridinehydrochloride;4-Piperazin-1-yl-2-{[4-trifluoromethyl)phenyl]sulfonyl}thieno[3,2-c]pyridinehydrochloride;2-[[2-tert-Butylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;2-[(3,4-Dichlorophenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamidehydrochloride;2-[(4-tert-Butylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride; 2-(1-Naphthylsulfonyl)-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride;2-[(3-Fluorophenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamidehydrochloride; 2-(Mesitylsulfonyl)-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;2-[(2-Methoxyphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;2-[(2,4-Dimethoxyphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;2-[(2,4-Dimethylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;2-[(2,5-Dimethylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;2-[(2-Ethylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;4-(Piperazinyl)-2-(3-methoxybenzyl-sulfonyl)-thienopyridinehydrochloride; 2-(Benzylsulfonyl)-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;4-Piperazin-1-yl-2-{[4-(trifluoromethyl)benzyl]sulfonyl}thieno[3,2-c]pyridinehydrochloride;2-[(3-Bromobenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;2-[(2,3-Difluorobenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;2-[(4-Bromobenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;2-{[2,5-bis(Trifluoromethyl)benzyl]sulfonyl}-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;2-[(4-Methylbenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;2-{[5-Chloro-2-(trifluoromethyl)benzyl]sulfonyl}-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;2-[(3,5-Dimethoxybenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;2-[(2-Naphthylmethyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridinehydrochloride;4-Piperazin-1-yl-2-{[4-(1,2,3-thiadiazol-4-yl)benzyl]sulfonyl}thieno[3,2-c]pyridinehydrochloride;1-(4-Pyrrolidin-1-ylphenyl)-2-[(4-piperazine-1-ylthieno[3,2-c]pyridin-2-yl)sulfonyl]ethanonehydrochloride; or1-[4-(Diethylamino)phenyl]-2-[(4-piperazine-1-ylthieno[3,2-c]pyridin-2-yl)sulfonyl]ethanonehydrochloride.
 33. The compound of claim 17, wherein the compound is:1-(4-Methylphenylsulphonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridinehydrochloride;1-(3-Chloro-2-methylphenylsulphonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridinehydrochloride;1-(3,4-Dimethoxyphenylsulphonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridinehydrochloride;4-(4-Piperazin-1-yl-pyrrolo[3,2-c]pyridine-1-sulfonyl)-benzonitrilehydrochloride;1-(4,5-Dichloro-thiophene-2-sulfonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridinehydrochloride;1-(2-Chloro-4-fluorophenylsulphonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridinehydrochloride;1-Phenylmethanesulfonyl-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridinehydrochloride;1-(5-Chloro-thiophene-2-sulfonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridinehydrochloride;1-(4-Butyl-benzenesulfonyl)-4-piperazin-1-yl-1H-pyrrolo(3,2-c)pyridinehydrochloride;1-(4-Phenoxy-benzenesulfonyl)-4-piperazin-1-yl-1H-pyrrolo(3,2-c)pyridinehydrochloride;1-(Phenylsulfonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridinehydrochloride;1-[(4-Chlorophenyl)sulfonyl]-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridinehydrochloride;1-[(4-Methoxyphenyl)sulfonyl]-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridinehydrochloride;1-[(2-Methoxy-5-methylphenyl)sulfonyl]-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridinehydrochloride; or4-Piperazin-1-yl-1-{[2-(trifluoromethyl)phenyl]sulfonyl}-1H-pyrrolo[3,2-c]pyridinehydrochloride.
 34. The compound of claim 23, wherein the compound is:N-(4-Methylphenyl)-4-(4-methylpiperazin-1-yl)thieno[3,2-c]pyridine-2-sulfonamidehydrochloride;2-Bromo-4-(4-methyl-piperazin-1-yl)-thieno[3,2-c]pyridine-3-sulfonicacid p-tolylamide hydrochloride;4-(4-Methylpiperazin-1-yl)-n-phenylthieno[3,2-c]pyridine-2-sulfonamidehydrochloride; 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid(3-fluoro-5-trifluoromethyl-phenyl)amide hydrochloride;4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid(4-chloro-phenyl)-amide hydrochloride;4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid(4-isopropyl-phenyl)-amide hydrochloride;4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid p-tolylamidehydrochloride;4-(4-Methylpiperazin-1-yl)-N-(2-cyclohex-1-en-1-ylethyl)thieno[3,2-c]pyridine-2-sulfonamidehydrochloride;2-(4-(4-Methylpiperazin-1-yl)thieno[3,2-c]pyridin-2-ylsulfonyl)-1,2,3,4-tetrahydroisoquinolinehydrochloride;4-(4-Methylpiperazin-1-yl)-N-(2-thien-2-ylethyl)thieno[3,2-c]pyridine-2-sulfonamidehydrochloride;4-(4-Methylpiperazin-1-yl)-N-[1-(1-naphthyl)ethyl]thieno[3,2-c]pyridine-2-sulfonamidehydrochloride;4-(4-Methylpiperazin-1-yl)-N-(4-hexylphenyl)thieno[3,2-c]pyridine-2-sulfonamidehydrochloride;N-(3-Chlorobenzyl)-4-(4-methylpiperazin-1-yl)thieno[3,2-c]pyridine-2-sulfonamide;4-(4-Methylpiperazin-1-yl)-N-[1-(4-fluorophenyl)ethyl]thieno[3,2-c]pyridine-2-sulfonamidehydrochloride;N-(2,3-Difluorobenzyl)-4-(4-methylpiperazin-1-yl)thieno[3,2-c]pyridine-2-sulfonamidehydrochloride;4-(4-Methylpiperazin-1-yl)-N-(4-chloro-2,5-dimethoxyphenyl)thieno[3,2-c]pyridine-2-sulfonamidehydrochloride;2-Bromo-4-(4-methylpiperazin-1-yl)-N-(2-cyclohex-1-en-1-ylethyl)thieno[3,2-c]pyridine-3-sulfonamidehydrochloride;2-Bromo-4-(4-methylpiperazin-1-yl)-N-[(1S)-1-(2-naphthyl)ethyl]thieno[3,2-c]pyridine-3-sulfonamidehydrochloride;2-Bromo-4-(4-methylpiperazin-1-yl)-N-[1-(4-fluorophenyl)ethyl]thieno[3,2-c]pyridine-3-sulfonamidehydrochloride;2-Bromo-4-(4-methylpiperazin-1-yl)-N-(2,4,5-trimethoxyphenyl)thieno[3,2-c]pyridine-3-sulfonamide;N-(3,4-Dichlorophenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamidehydrochloride;N-(2,4-Difluorophenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamidehydrochloride;4-Piperazin-1-yl-N-[-3-(trifluoromethyl)phenyl]thieno[3,2-c]pyridine-2-sulfonamidehydrochloride;N-(3-Ethylphenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamidehydrochloride;N-(3,4-Dimethoxyphenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamidehydrochloride;N-(4-Bromo-2-methylphenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamidehydrochloride;2-(4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonyl)-1,2,3,4-tetrahydro-isoquinolinehydrochloride; 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid(2-thiophen-2-yl-ethyl)-amide hydrochloride;4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid(4-chloro-2,5-dimethoxy-phenyl)amide hydrochloride;4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid phenethyl-amidehydrochloride; 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid(2,6-diethyl-phenyl)-amide hydrochloride;4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid(3-phenyl-propyl)-amide hydrochloride;4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid(3,3-diphenyl-propyl)-amide hydrochloride;4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid[2-(5-methoxy-1H-indol-3-yl)-ethyl]-amide hydrochloride;4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid4-trifluoromethyl-benzylamide hydrochloride;4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acidbenzyl-ethyl-amide hydrochloride;N-(3-Ethylphenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-3-sulfonamidehydrochloride;N-(4-Isopropylphenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-3-sulfonamidehydrochloride;N-(4-Methylphenyl)-4-(pyrrolidin-3-yloxy)thieno[3,2-c]pyridine-2-sulfonamidehydrochloride;N-(4-Methylphenyl)-4-(piperidin-4-yloxy)thieno[3,2-c]pyridine-2-sulfonamidehydrochloride;N-(2,3-Difluorobenzyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamidehydrochloride;N-(3-Chlorobenzyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamidehydrochloride; 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acidphenylamide hydrochloride;4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid(4-tert-butyl-phenyl)-amide hydrochloride;4-(4-Methyl-piperazin-1-yl)-thieno[3,2-c]pyridine-2-sulfonic acidphenylamide hydrochloride;4-(4-Methyl-piperazin-1-yl)-thieno[3,2-c]pyridine-2-sulfonic acid(3-chloro-phenyl)-amide hydrochloride;2-Bromo-4-(4-methyl-piperazin-1-yl)-thieno[3,2-c]pyridine-3-sulfonicacid phenylamide hydrochloride;4-(4-Methyl-piperazin-1-yl)-thieno[3,2-c]pyridine-3-sulfonic acid(4-methylphenyl)-amide hydrochloride; orN-Phenyl-7-piperazin-1-ylthieno[2,3-c]pyridine-2-sulfonamidehydrochloride.
 35. A compound of claim 24, wherein the compound is:N-(4-methylphenyl)-4-piperazin-1-ylfuro[3,2-c]pyridine-2-sulfonamidehydrochloride;N-phenyl-4-piperazin-1-ylfuro[3,2-c]pyridine-2-sulfonamidehydrochloride; orN-phenyl-7-piperazin-1-ylfuro[2,3-c]pyridine-2-sulfonamidehydrochloride.
 36. A compound according to claim 25, which is thecompound 4-Piperazin-1-yl-thiazolo[4,5-c]pyridine-2-sulfonic acidphenylamide hydrochloride.
 37. A compound according to claim 26, whichis the compoundN-(4-methylphenyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridine-2-sulfonamidehydrochloride;N-phenyl-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridine-2-sulfonamidehydrochloride; orN-phenyl-7-piperazin-1-yl-1H-pyrrolo[2,3-c]pyridine-2-sulfonamidehydrochloride.
 38. A compound of claim 27, wherein the compound is:4-Chloro-N-[4-(pyrrolidin-3-yloxy)-1-naphthyl]benzenesulfonamidehydrochloride;4-Methoxy-N-[4-(pyrrolidin-3-yloxy)-1-naphthyl]benzenesulfonamidehydrochloride;5-Chloro-N-[4-(pyrrolidin-3-yloxy)-1-naphthyl]thiophene-2-sulfonamidehydrochloride;4-Chloro-N-[4-(piperidin-3-yloxy)-1-naphthyl]benzenesulfonamidehydrochloride;4-Methoxy-N-[4-(piperidin-3-yloxy)-1-naphthyl]benzenesulfonamidehydrochloride;5-Fluoro-2-methyl-N-[4-(piperidin-4-yloxy)-1-naphthyl]benzenesulfonamidehydrochloride;5-Chloro-N-[4-(piperidin-4-yloxy)-1-naphthyl]thiophene-2-sulfonamidehydrochloride;4-Chloro-N-{4-[(3S)-pyrrolidin-3-yloxy]-1-naphthyl}benzenesulfonamidehydrochloride; or4-Chloro-N-{4-[(3R)-pyrrolidin-3-yloxy]-1-naphthyl}benzenesulfonamidehydrochloride.
 39. A method for preparing a compound of formula (I) ofclaim 1, the method comprising: (a) contacting 4-nitro-1-naphthol withBoc-protected 3-hydroxypyrrolidine or 4-hydroxypiperidine to form anitronaphthalene product (b) reducing the nitro group in thenitronaphthalene product obtained in step (a) to form anaminonaphthalene derivative; and (c) contacting the aminonaphthaleneobtained in step (b) with a sulfonyl chloride to form a sulfonamide. 40.A method for preparing a compound of formula (I) of claim 1, wherein Pis

, the method comprising: preparing a heteroaromatic 5-member ring fusedhalogen-substituted pyridine, reducing an aromatic nitro group to forman amino group; substituting the amino group with a thiol via a diazointermediate; oxidizing the thiol derivative to a sulphone; introducinga halogen atom by electrophilic aromatic substitution; and substitutingthe introduced halogen atom with a diamine.
 41. A method for preparing acompound of formula (I) of claim 1, wherein P is

the method comprising: preparing a heteroaromatic 5-member ring fusedpyridine; introducing a carboxylic moiety; converting the carboxylicmoiety to an amine by Curtius rearrangement; contacting the amine groupwith a sulphonylchloride.
 42. A process for the preparation of acompound of formula (I) of claim 1, wherein P is

the method comprising: preparing a heteroaromatic 5-member ring fusedpyridine; introducing a sulfonylchloride moiety by nucleophilicaddition; contacting the sulphonylchloride moiety with an aniline toobtain a sulfonamide; substituting a chloro with a diamine.
 43. Apharmaceutical composition comprising a compound of formula (I) of claim1 and a pharmaceutically acceptable diluent or carrier.
 44. Thepharmaceutical composition of claim 43, wherein A and B together arenaphthyl, P has formula (a) or (c) and is attached to position 7 on thenaphthyl ring, and R³ is attached to position 1 on the naphthyl ring.45. The pharmaceutical composition of claim 43, wherein the compound ispresent in an effective amount for the treatment or prophylaxis ofdisorders of the central nervous system and/or 5-HT₆ receptor relateddisorders, to achieve reduction of body weight and body fat.
 46. Thepharmaceutical composition of claim 45, wherein A and B are together arenaphthyl, P has formula (a) or (c) and is attached to position 7 on thenaphthalene ring, R³ is substituted in position 1 on the naphthalenering, and the 5-HT₆ receptor related disorder is type II diabetes. 47.The pharmaceutical composition of claim 45, wherein D is a pyrrole ring,P has formula (c), R³ is of the formula

substituted in position 3 on the pyrrole ring, and the 5-HT₆ receptorrelated disorder is type II diabetes.
 48. The pharmaceutical compositionof claim 45, wherein D is a pyrrole ring, P has formula (c), R³ isselected from

and is substituted at position 3 of the pyrrole ring, and the 5-HT₆receptor related disorder is obesity.
 49. A method for the treatment orprophylaxis of a 5-HT₆ receptor related disorder in a subject in need ofsuch treatment or prophylaxis, the method comprising administering tothe subject an effective amount of a compound of formula (I) of claim 1.50. The method of claim 49, wherein A and B together are naphthyl, P hasformula (a) or (c) and is attached to position 7 on the naphthalenering, and R³ is attached to position 1 on the naphthalene ring.
 51. Amethod for the treatment or prophylaxis of disorders of the centralnervous system in a subject in need of such treatment or prophylaxis,the method comprising administering to the subject an effective amountof a compound of formula (I) of claim
 1. 52. A method for the treatmentor prophylaxis of type II diabetes in a subject in need of suchtreatment or prophylaxis, the method comprising administering to thesubject an effective amount of a compound of formula (I) of claim
 1. 53.The method of claim 52, wherein A and B together are naphthyl, P hasformula (a) or (c) and is attached to position 7 on the naphthalenering, and R³ is attached to position 1 on the naphthalene ring.
 54. Themethod of claim 52, wherein D is a pyrrole ring, P has formula (c), andR³ is selected from

wherein R³ is attached to position 3 on the pyrrole ring.
 55. A methodfor the treatment or prophylaxis of obesity and to achieve reduction ofbody weight and of body weight gain in a subject in need of suchtreatment or prophylaxis, the method comprising administering to thesubject an effective amound of a compound of formula (I) of claim
 1. 56.The method of claim 55, wherein D is a pyrrole ring, P has formula (c),and R³ is selected from: wherein R³ is attached to position 3 on thepyrrole ring.


57. A method for modulating 5-HT₆ receptor activity in a subject in needof such modulating, the method comprising administering to the subjectan effective amount of a compound of formula (I) of claim 1.